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| United States Patent |
5,750,754
|
|
Mills
|
May 12, 1998
|
Heterocyclic compounds
Abstract
A compound of the general formula
(M.sup.1).sub.n -Q-(M.sup.2).sub.1-n -L-A I
wherein: n is 0 or 1;
M.sup.1 is an amino group;
Q is an aromatic heterocyclic group containing a basic nitrogen atom;
M.sup.2 is an imino group;
L is a template group; and
A is an acidic group, or an ester or amide derivative thereof, or a
sulphonamide group;
and pharmaceutically acceptable salts and pro-drugs thereof, for use in the
treatment of a disease in which platelet aggregation mediated by the
binding of adhesion molecules to GPIIb-IIIa is involved and the optically
active compound
(-)-(3R)-3-methyl-4-{4-4-(4-pyridyl)-piperazin-1-yl!phenoxy}butyric acid
is also disclosed.
| Inventors:
|
Mills; Stuart D. (Cheshire, GB2)
|
| Assignee:
|
Zeneca Limited (London, GB)
|
| Appl. No.:
|
658097 |
| Filed:
|
June 4, 1996 |
Foreign Application Priority Data
| Mar 29, 1993[GB] | 9306451 |
| Mar 29, 1993[GB] | 9306453 |
| Dec 15, 1993[GB] | 9325605 |
| Dec 15, 1993[GB] | 9325610 |
| Sep 07, 1995[GB] | 9518188 |
| Current U.S. Class: |
558/52; 560/179 |
| Intern'l Class: |
C07C 309/07 |
| Field of Search: |
560/179
558/52
|
References Cited
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| 4194 | Mar., 1995 | ZW.
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| 4294 | Mar., 1995 | ZW.
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Other References
Vogel et al, Chem. Abst, vol. 97, #92,034Z (1982).
Alig. et al., "Low Molecular Weight, Non-peptide Fibrinogen Receptor
Antagonists", J. Med. Chem., 1992, 32, 4393-4407.
Harman, et al., "Non-peptide Fibrinogen Receptor Antagonists 1. Discovery
and Design of Exosite Inhibitors", J. Med. Chem., 1992, 35, 4640-4642.
Catto, et al., 1-(2-Pyrindinyl)piperazine Derivatives with
Antianaphylactic, Antibronchospastic, and Mast Cell Stabilizing
Activities, J. Med. Chem. 1987, 30, 13-19.
Chemical Abstract, 98, 125889b; Derwent Abstract 82-1-248J; Registery No.=
85000-31-3; all abstracts of JP57,183,738 (82,183,738). Nov. 1992.
Sammes, et al., "Synthetic Applications of N-N Linked Heterocycles, Part
15..sup.1 A Facile Synthesis of 4-Pyridyl-(aryl)amines via the Reaction
Between 4-Chloro-1-pyridiniopyridinium Salts and Aryl Amines", J. Chem.
Soc., Perkin I, 1983-973-978.
|
Primary Examiner: Reamer; James H.
Attorney, Agent or Firm: Cushman Darby & Cushman Intellectual Property Group of Pillsbury Madison &
Sutro LLP
Claims
I claim:
1. The optically active compound tert-butyl
(3R)-3-methyl-4-hydroxybutyrate, or a derivative thereof reactive in the
formation of an ether linkage by nucleophilic substitution with a phenolic
compound, substantially free of the (3S) stereoisomer.
2. A compound according to claim 1, wherein the reactive derivative is
tert-butyl (3R)-3-methyl-4-(p-toluenesulphonyloxy)butyrate.
Description
The present invention relates to a group of heterocyclic compounds which
inhibit cell adhsion (for example, platelet aggregation), to processes for
their preparation and to pharmaceutical compositions containing them.
A variety of diseases involve cell adhesion during their development. For
example, platelet aggregation is involved in the formation of blood
thrombi, which can lead to diseases such as thrombosis, (e.g. stroke and
thrombotic events accompanying unstable angina and transient ischaemic
attack), myocardial infarction, atherosclerosis, thromboembolism and
reocclusion during and after thrombolytic therapy.
It is widely believed that the platelet membrane glycoprotein IIb/IIIa
(GPIIb/IIIa) mediates platelet aggregation. Adhesion molecules such as
fibrinogen and von Willebrand Factor are believed to bind to GPIIb/IIla
sites on adjacent platelets and thereby cause them to aggregate. Other
adhesion molecules which are known to bind to the GPIIb/IIIa are
fibronectin, vitronectin and thrombospondin.
Compounds which inhibit platelet aggregation and the binding of adhesion
molecules to GPIIb/IIIa are known. Commonly these compounds are based upon
the binding sites of the adhesion molecules, which are peptides. For
example, the portion of fibrinogen which is believed to bind to GPIIb/IIIa
is the amino acid sequence RGD. This sequence may be viewed as comprising
an arginine group separated from an acidic group by a template group.
Surprisingly, as a result of random screening, the ability to inhibit
platelet aggregation and to inhibit the binding of fibrinogen to
GPIIb/IIIa has now been found to be possessed by certain heterocyclic
compounds containing a 4-(4-pyridyl)piperazin-1-yl or related group.
According to one aspect, therefore, the present invention provides a
compound of the general formula
(M.sup.1).sub.n -Q-(M.sup.2).sub.1-n -L-A (I)
wherein n is 0 or 1;
M.sup.1 is an amino group;
Q is an aromatic heterocyclic group containing a basic nitrogen atom;
M.sup.2 is an imino group;
L is a template group; and
A is an acidic group, or an ester or amide derivative thereof, or a
sulphonamide group;
and pharmaceutically acceptable salts and pro-drugs thereof, for use in the
treatment of a disease in which platelet aggregation mediated by the
binding of adhesion molecules to GPIIb-IIIa is involved.
Without wishing to be bound by theory, it is believed that the basic
nitrogen atom in the aromatic heterocyclic group represented by Q
functions as a replacement for the strongly basic guanidine group in
arginine. The function of the nitrogen atom which is attached to Q in the
amino group represented by M.sup.1 or the imino group represented by
M.sup.2 is believed to be to contribute to the ability of the nitrogen
atom in Q to function as a base. For example, when (M.sup.1).sub.n
-Q-(M.sup.2).sub.1-n represcnts a 4-(4-pyridyl)piperazin-1-yl group, the
nitrogen atom in the piperazin-1-yl group is believed to contribute to the
ability of the nitrogen atom in the pyridyl group to function as a base as
shown below:
##STR1##
As will be described in more detail hereinafter, the group (M.sup.1).sub.n
-Q-(M.sup.2).sub.1-n has been found to be associated with ability to
antagonise the binding of fibrinogen to GPIIb/IIa when combined with an
acidic or sulphonamide group and a wide variety of template groups. Ester
and amide derivatives of the acids have also been found to be active, but
generally with lower potency than the acids. This activity may be due to
the intrinsic activity of the compounds or to their hydrolysis to the
corresponding acids in the test systems used. The group (M.sup.1).sub.n
-Q-(M.sup.2).sub.1-n has also been found to be associated with a
favourable effect on bioavailability. Certain of the compounds of formula
I have been found to possess particularly good activity on oral
administration. Commonly, esters and amides have been found to possess
superior oral activity to their parent acids.
In the compounds of formula I, M.sup.1 is an amino group, including
--NR.sup.1 R.sup.2 in which R.sup.1 and R.sup.2 are each independently
hydrogen or (1-4C)alkyl or together form (4-5C)alkylene. Examples of
values for R.sup.1 and R.sup.2 are hydrogen and methyl. Examples of values
for --NR.sup.1 R.sup.2 are dimethylamino and pyrrolidin-1-yl.
Q is an aromatic heterocyclic group containing a basic nitrogen atom,
including imidazoly, pyridyl, pyrimidyl, pyrazinyl, quinolyl and purinyl,
optionally substituted by one or more substituents, including (1-4C)alkyl,
(1-4C)alkoxy, halogeno, and (3-4C)alkylene which, together with the two
atoms to which it is attached forms a ring. Examples of values for the
aromatic heterocyclic group are 2-imidazolyl, 4-imidazolyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, 4-pyrimidyl, 2-pyrazinyl, 2-quinolinyl, 4-quinolinyl
and 6-purinyl. Examples of values for optional substituents are: for
(1-4C)alkyl, methyl; for (1-4C)alkoxy, methoxy; for halogeno, chloro and
bromo; and for (3-4C)alkylene, butylene. Examples of values for Q are
3-pyridyl; 4-pyridyl; 2-methyl-4-pyridyl; 2,6-dimethyl-4-pyridyl:
4-pyrimidyl; 4-(5,6,7,8-tetrahydro)quinolinyl; 4-quinolinyl and
2-methyl-4-quinolinyl. Preferably, when Q is pyridyl, pyrimidyl,
pyrazinyl, quinolyl or purinyl, the basic nitrogen atom contained by Q is
located at the 4-position relative to M.sup.1, when n is 1, or M.sup.2,
when n is 0. Q is preferably 4-pyridyl, optionally substituted as defined
hereinabove.
M.sup.2 is an imino group; including --NR.sup.3 -- in which R.sup.3 is
hydrogen, (1-4C)alkyl or a (2-3C)alkylene bridge attached to Q; and
--NR.sup.4 -D-TR.sup.5 -- in which
(i) T is N; D is CH.sub.2 CO; CH.sub.2 SO.sub.2 ; (2-3C)alkylene optionally
substituted by carboxy, (1-4C)alkoxycarbonyl, (1-4C)alkoxymethyl or a
(2-3C)alkylene bridgc attached to Q; and R.sup.4 and R.sup.5 together
represent (2-3C)alkylene or CH.sub.2 CO, or each independently represents
hydrogen or (1-4C)alkyl or R.sup.5 represents hydrogen or (1-4C)alkyl and
R.sup.4 represents (2-3C)alkylene attached to Q; or
(ii) T is CH; D is CH.sub.2 CO, CH.sub.2 CH.sub.2 NH, (1-3C)alkylene
optionally substituted by carboxy or (1-4C)alkoxycarbonyl, or
(2-3C)alkyleneoxy; and R.sup.4 and R.sup.5 together represent
(1-3C)alkylene; or
(iii) R.sup.4 and --D-TR.sup.5 -- together form a (5-6C)alkenylene group.
Examples of values for --NR.sup.3 -- when R.sup.3 is hydrogen or
(1-4C)alkyl are NH and methylimino.
Examples of values for the group Q-M.sup.2 when M.sup.2 is a group of
formula --NR.sup.3 -- in which R.sup.3 is a (2-3C)alkylene bridge attached
to Q are 1,2,3,4-tetrahydro-1,6-naphthyridin-1-yl and
pyrrolo3,2-c!pyridin-1-yl.
Examples of values for --NR.sup.4 -D-TR.sup.5 -- when T is N are
5-oxoimidazolidin-1,3-diyl; 2-oxopiperazin-1,4-diyl,
2,6-dioxopiperazin-1,4-diyl, 1,1-dioxo-1,2,5-thiadiazin-2,5-diyl,
piperazin-1,4-diyl, 2-carboxypiperazin-1,4-diyl,
3-carboxypiperazin-1,4-diyl, 2-methoxycarbonylpiperazin1,4-diyl,
3-methoxycarbonylpiperazin-1,4-diyl, 2-methoxymethylpiperazin-1,4-diyl,
3-methoxymethylpiperazin-1,4-diyl and
N-2-(N'-methyl)aminoethyl(N-methyl)amino.
Examples of values for Q-M.sup.2 when T is N and D is (2-3C)alkylene
optionally substituted by a (2-3C)alkylene bridge attached to Q include
1,2,3,4-tetrahydro-1,6-naphthyridin-2-yl and
pyrrolo3,2-c!pyridin-2-ylethylamino.
Examples of values for --NR.sup.4 -D-TR.sup.5 -- when T is CH are
pyrrolidin-3,1-diyl, 3-oxo-pyrrolidin-4,1-diyl
2-carboxypyrriolidin-4,1-diyl, 2-methoxycarbonylpyrrolidin-4,1-diyl,
2-ethoxycarbonylpyrrolidin-4,1-diyl, piperidin-3,1-diyl,
piperidin-4,1-diyl, piperazin-2,4-diyl and morpholin-2,4-diyl.
An example of a group of formula --NR.sup.4 -D-TR.sup.5 -- in which R.sup.4
and --D-TR.sup.5 -- together form a (5-6C)alkenylene group is
1,2,3,6-tetrahydropyridin-4,1-diyl.
Particularly preferred values for M.sup.2 are piperazin-1,4-diyl,
piperidin-4,1-diyl and 2-oxo-piperazin-1,4-diyl.
Preferably n is 0.
Accordingly, particularly preferred values for the group (M.sup.1).sub.n
-Q-(M.sup.2).sub.1-n are 4-(4-pyridyl)piperazin-1-yl,
4-(4-pyridyl)-2-oxopiperazin-1-yl and 1-(4-pyridyl)piperidin-4-yl.
L is a template group, including (4-7C)alkylene and a group of formula
X.sup.1 -Y-X.sup.2 in which X.sup.1 is a bond or a linking group,
including (1-4C)alkylene, (2-4C)alkenylene, (2-4C)alkynylene,
(1-2C)alkylenephenylene, phenyleneoxy, phenyleneoxymethylene,
phenylenecarbonyl, phenyleneCONH, (1-3C)alkylenecarbonyl,
(1-2C)alkylenecarbonyl substituted by benzyl or p-hydroxybenzyl,
methylidenepylrrolidin-1-ylacetyl, (1-2C)-alkylenecarbonyloxy,
(1-2C)alkyleneCONH, (1-2C)alkyleneCONH(1-2C)alkyleneCO,
(1-2C)alkyleneCONH(1-2C)alkyleneCONH, benzyl(1-2C)alkyleneCONH,
(1-4C)alkyleneoxy, (1-2C)alkyleneoxy(1-2C)alkylene,
(1-2C)alkyleneoxy(1-2C)alkylenecarbonyl, (1-3C)alkyleneCH(OH), and, when
M.sup.2 is --NR.sup.4 -D-TR.sup.5 --, carbonyl, carbonyl(1-3C)alkylene,
CONH, (1-2C)alkyleneNHCO and CONH(1-3C)alkylene, and when T is CH, oxy,
oxy(1-3C)alkylene, oxy(1-2C)alkylenecarbonyl or
oxy(1-2C)alkylenephenylene; or, when n is 0, X.sup.1 together with M.sup.2
may form a group of formula
##STR2##
Examples of values for X.sup.1 are a bond, methylene, ethylene, propylene,
1-methylethylene, ethenylene, ethynylene, methylenephenylene,
phenyleneoxy, phenyleneoxymethylene, phenylenecarbonyl, phenyleneCONH,
methylenecarbonyl, ethylenecarbonyl,1-methylethylenecarbonyl,
ethylidinecarbonyl, 2-propylidinecarbonyl, benzylmethylenecarbonyl,
p-hydroxybenzylmethylenecarbonyl, methylidenepyrrolidin-1-ylacetyl,
methylenecarbonyloxy, methyleneCONH, methyleneCONHmethyleneCONH,
benzylmethyleneCONH, methyleneoxy, ethyleneoxy, propyleneoxy, butylencoxy,
methyleneoxymethylene, methyleneoxymethylenecarbonyl, methyleneCH(OH),
and, when M.sup.2 is --NR.sup.4 -D-TR.sup.5 --, carbonyl,
carbonylmethylene, carbonylethylene, CONH, methyleneNHCO, CONHmethylene,
and when T is CH; oxy, oxymethylene, methyleneNHCO, oxymethylenecarbonyl
and oxymethylenephenylene. Particularly preferred values for X.sup.1
include methylenecarbonyl, ethylenecarbonyl ethylidinecarbonyl, carbonyl,
carbonylethylene, methyleneoxy, ethyleneoxy and, when M.sup.2 is
--NR.sup.4 -D-TR.sup.5 -- and T is CH; oxy.
Y is a cyclic group, including groups of formulae:
##STR3##
in which m is 0 or 1, p is 1 or 2, q is 0,1,2 or 3, Z.sup.1, Z.sup.1a and
Z.sup.2 represent hydrogen or optional substituents, including hydroxy,
halogeno, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy,
(1-4C)alkylthio, (2-4C)alkenyloxy, nitro, amino, (1-4C)alkylamino,
(2-4C)alkanoylamino, cyano and (1-4C)alkoxycarbonyl, or have one of the
meaniigs given for X.sup.2 -A, Z.sup.3 represents hydrogen or hydroxy,
R.sup.7 is hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl, R.sup.8 is as
defined for R.sup.7, and E is O, S or NH; and R.sup.11 is hydrogen,
(1-4C)alkyl, phenyl(1-4C)alkyl or a group of formula X.sup.2 -A; or Y is
an amide-containing group, including CONR.sup.22, NR.sup.22 CO and a group
of formula
##STR4##
in which R.sup.22 represents hydrogen, (1-4C)alkyl or phenyl(1-2C)alkyl.
Preferred groups of formula (a) are groups in which X.sup.1 and X.sup.2 are
attached respectively at the 1 and 3 or 1 and 4 positions. Z.sup.1 is
preferably located ortho to X.sup.2 ; that is to say at the 2 or 6
position. Examples of such groups include 1,3-phenylene,
5-methoxycarbonylmethoxy-1,3-phenylene, 5-carboxymethoxy-1,3-phenylene,
1,4-phenylene, 2-methoxy-1,4-phenylene, 3-methoxy-1,4-phenylene,
2,6-dichloro-1,4-phenylene, 2,6-di-tert-butyl-1,4-phenylene,
2-carboxymethoxy-1,4-phenylene, 2-methoxycarbonylmethoxy-1,4-phenylene and
2-ethoxycarbonylmethoxy-1,4-phenylene, 3-methyl-1,4-phenylene,
2-allyl-1,4-phenylene, 2-propyl-1,4-phenylene, 2-nitro-1,4-phenylene,
2-methyl-1,4-phenylene, 3-methoxycarbonylmethoxy-1,4-phenylene,
3-ethoxycarbonylmethoxy-1,4-phenylene, 3-carboxymethoxy-1,4-phenylene, and
2-tert-butyloxycarbonylmnethyloxy-1,4-phenylenie.
Examples of values for Z.sup.1, Z.sup.1a and Z.sup.2 are hydrogen, hydroxy,
chloro, fluoro and bromo, methyl, ethyl, propyl, t-butyl, allyl, methoxy,
methylthio, allyloxy, nitro, cyano, methoxycarbonyl, carboxymethoxy,
methoxycarbonylmethoxy, ethoxycarbonylmethoxy and
tert-butyloxycarbonylmethoxy.
Examples of values for R.sup.7, R.sup.8 and R.sup.11 are hydrogen, methyl
and benzyl.
When Y is a group of formula (c), preferably m is 0 and p is 2.
Y is preferably a 1,2-, 1,3- or 1,4-phenylene group of formula (a); a
napth-1,6-diyl group of formula (b); a piperidin-4,1-diyl group of formula
(c) a 4-quinolon-3,7-diyl group of formula (d); a tetralon-6,2-diyl group
of formula (e); a benzofuran-2,5-diyl group of formula (f); a
4-quinolon-7,3-diyl group of formula (i); a cyclohexa-4,1-diyl group of
formula (k); a piperidin-3,1-diyl group of formula (1); a pyridin-2,5-diyl
or pyridin-2,6-diyl group of formula (m); a quinolin-6,2-diyl or
quinolin-6,4-diyl group of formula (n); a naphth-1,4-diyl group of formula
(o); a 2-pyridon-4,1-diyl group of formula (p); a 4-pyridon-2,5-diyl group
of formula (q), a piperidin-1,4-diyl group of formula (r); a
cyclohexa-3,1-diyl group of formula (s); a piperidin-1,3-diyl group of
formula (t), CONH, NHCO or a 2-carboxyethylidinecarboxamido group.
Examples of values for Y are 1,2-phenylene; 1,3-phenylene;
5-methoxycarbonyl-1,3-phenylene; 1,4-phenylene;
2,6-dichloro-1,4-phenylene; 2-methyl-1,4-phenylene;
2-propyl-1,4-phenylene; 2-allyl-1,4-phenylene;
2,6-di-tert-butyl-1,4-phenylene; 2-methoxy-1,4-phenylene;
3-methoxy-1,4-phenylene; 2-carboxymethoxy-1,4-phenylene;
2-methoxycarbonylmethoxy-1,4-phenylene;
2-ethoxycarbonylmethoxy-1,4-phenylene;
2-tert-butyloxycarbonylmethoxy-1,4-phenylene; 3-c
arboxymethoxy-1,4-phenylene; 3-methoxycarbonylmethoxy-1,4-phenylene;
2-nitro-1,4-phenylene; naphth-1,6-diyl; piperidin-4,1-diyl;
3-carboxymethoxypiperidin-4,1-diyl; 1-ethyl-4-quinolon-3,7-diyl;
1-propyl-4-quinolon-3,7-diyl; tetralon-6,2-diyl; benzofuran-2,5-diyl;
1-benzyl-4-quinolon-7,3-diyl; 1-hydroxycyclohexa-1,4-diyl;
piperidin-3,1-diyl; pyridin-2,5-diyl; pyridin-2,6-diyl; quinolin-6,2-diyl;
quinolin-6,4-diyl; naphth-1,4-diyl; 2-pyridon-4,1-diyl;
1-benzyl-4-pyridon-2,5-diyl; piperidin-1,4-diyl; cyclohexa-3,1-diyl;
piperidin-1,3-diyl; CONH and 2-carboxyethylidenecarboxamido.
X.sup.2 is a bond or a linking group, including, (1-4C)alkylene,
(2-4C)alkenylene, oxy(1-4C)alkylene, oxy(5-6C)alkylene,
oxy(2-4C)alkenylene, thio(1-3C)alkylcne, SO.sub.2 (1-3C)alkylene,
amino(1-3C)alkylene, SO.sub.2 NH(1-3C)alkylene, NR.sup.21
CO(1-2C)alkylene, CONR.sup.21 (1-2C)alkylene (where R.sup.21 represents
hydrogen, (1-4C)alkyl or benzyl), in any of which the alkylene group may
optionally be substituted by (2-4C)alkenyl; (2-4C)alkynyl; (1-4C)alkoxy;
carboxy; (1-4C)alkoxycarbonyl; phenyl(1-4C)alkoxycarbonyl;
phenyl(1-2C)alkylNHCO; carboxy(1-2C)alkyl; phenyl(1-2C)alkyl;
phenylsulphonyl(1-2C)alkyl; pyridyl, phenyl; amino or a group of formula
NR.sup.12 XR.sup.6 in which X is SO.sub.2, CO or CO.sub.2 ; R.sup.12 is
hydrogen or (1-4C)alkyl and R.sup.6 is (1-6C)alkyl, (6-10C)aryl,
(6-10C)aryl(1-4C)alkyl, di(1-4C)alkylamino(1-4C)alkyl,
morpholino(1-4C)alkyl, piperidino(1-4C)alkyl or
N-(1-4C)alkylpipenidino(1-4C)alkyl.
Examples of values for X.sup.2 are a bond, methylene, ethylene, ethenylene,
oxymethylene, 2-oxyethylene, 3-oxypropylene, 2-oxyprop-2-ylene,
4-oxybutylene, 5-oxypentylene, thiomethylene, aminomethylene,
carboxamidomethylene, 2-carboxamidoethylene, 2-phenylethylidene,
oxy(imethoxycarbonyl )methylene,
1-(2-carboxyethyl)ethylene,1-(benzyloxycarbonyl)ethylene, and groups of
formula CH.sub.2 CH(NR.sup.12 XR.sup.6) such as
1-(butylsulphonylamino)ethylene CH.sub.2 CH(NHSO.sub.2 CH.sub.2 CH.sub.2
CH.sub.2 CH.sub.3) !, 1-(methylsulphonylamino)ethylene,
1-(benzylsulphonylamino)ethylene, 1-(p-toluenesulphonylamino)ethylene,
2-(butylsulphonylamino)ethylene, 2-(p-toluenesulphonylamino)ethylene,
3-oxy(1-(butylsulphonylamino)propylene), 2-carboxamido(2-phenyl)ethylene
and 2-carboxamidopropylene.
Examples of values for L when it represents (4-7C)alkylene include
butylene, pentylene and hexylene.
A is an acidic group, including carboxy or an ester or amide thereof, an
acyl sulphonamide group of formula CONHSO.sub.2 R.sup.9, including groups
in which R.sup.9 is (1-4C)alkyl or optionally substituted phenyl; a
1H-tetrazol-5-yl group or a sulphonamide group of formula NHSO.sub.2
R.sup.10 in which R.sup.10 is (1-6C)alkyl such as methyl or butyl;
fluoro(1-6C)alkyl such as trifluoromethyl; or phenyl unsubstituted or
substituted by one or two optional substituents selected from (1-4C)alkyl,
(1-4C)alkoxy and halogen; for example p-tolyl.
A is preferably a carboxy group, a (1-4C)alkoxycarbonyl group such as
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, or
tert-butoxycarbonyl, a (1-6C)alkylsulphonamide group such as
methanesulphonylamino, butylsulphonylaamino, or p-tolylsulphonylaimno.
Accordingly, particularly preferred groups of formula Y-X.sup.2 -A are
2-(4-phenoxy)acetic acid and 2,2'-(4-phenylene-1,2-dioxy)diacetic acid.
One group of compounds of particular interest is that of general formula Ia
##STR5##
in which M.sup.2, X.sup.1, Z.sup.1, Z.sup.1a and X.sup.2 are as defined
hereinabove; A is a carboxyl group or an ester thereof as defined
hereinabove, and R.sup.13 is hydrogen, (1-4C)alkyl, (1-4C)alkoxy or
halogen.
Another group of compounds of particular interest is that of general
formula Ib
##STR6##
in which T, X.sup.1, Z.sup.1, Z.sup.1a, X.sup.2, R.sup.13 and A are as
defined hereinabove.
Another group of compounds of particular interest is that of general
formula Ic
##STR7##
in which T, X.sup.1, Y, X.sup.2, R.sup.13 and A are as defined
hereinabove.
Another group of compounds of particular interest is that of general
formula Id
##STR8##
in which Q, M.sup.2, X.sup.1, Z.sup.1 and Z.sup.1a, are as defined
hereinabove, and the ester or amide derivative thereof and
pharmaceutically acceptable salts and pro-drugs thereof.
Another group of compounds of particular interest is that of general
formula Ie
##STR9##
in which X.sup.1, X.sup.2, R.sup.13, m, p and A are as defined
hereinabove.
Another group of compounds of particular interest is that of general
formula If
##STR10##
in which T, X.sup.1, Y, X.sup.2, R.sup.13 and R.sup.10 are as defined
hereinabove.
Examples of values for R.sup.13 are methyl, methoxy and chloro.
A particularly preferred group of compounds is that of formula Ia in which
M.sup.2 is piperazin-1,4-diyl, piperidin-4,1-diyl or
2-oxopiperazin-1,4-diyl.
Two preferred sub-groups of compounds of formula Ia may be identified. One
consists of those compounds of formula Ia in which X.sup.1 represents a
bond. In this sub-group, X.sup.2 preferably represents an
oxy(2-4C)alkylene group, especially an oxypropylene group, optionally
substituted on the alkylene group as defined hereinabove. The other
consists of those compounds of formula Ia in which X.sup.2 represents
oxymethylene. In this sub-group X.sup.1 preferably represents
methylenecarbonyl.
Examples of specifically preferred compounds are those of Examples 1, 2,
50, 51, 61, 62, 240, 241, 242 and 243 herein.
Examples of ester derivatives of a carboxy group are esters formed with
alcohols such as (1-6C)alkanols, for example methanol, ethanol, propanol,
isopropanol and tert.butanol; indanol; adamantol;
(1-6C)alkanoyloxy(1-4C)alkanols such as pivaloyloxymethanol; glycolamides;
(S-methyl-2-oxo-1,3-dioxol-4-yl)methyl alcohol; and
(1-4C)alkoxycarbonyl(1-4C)alkanols. It will be appreciated that compounds
of formula I in which Y is a group of formula (a) or (b) in which Z.sup.1
or Z.sup.2 is hydroxy may form internal esters. An example of such an
internal ester is a compound in which X.sup.1.Y.X.sup.2.A represents:
##STR11##
Examples of amide derivatives of a carboxy group include amides derived
from ammonia or amines such as (1-4C)alkylamines, for example methylamine;
di(1-4C)alkylamines); C(1-4C)alkoxy(1-4C)alkylamines such as
methoxyethylaminie; phenyl(1-2C)alkylamines such as benzylamine; and amino
acids such as glycine or an ester thereof.
Examples of pro-drugs of compounds of formula I include compounds
possessing metabolically labile groups, in other words groups that are
cleaved in vivo to afford a compound of formula I. Such groups include
metabolically labile ester and amide derivatives. It will be appreciated
that certain of the compounds of general formula I are in the form of
enantiomers. It will be understood that the invention includes any
enantiomer which has the property of inhibiting platelet aggregation and
the binding of adhesion molecules to GPIIb-IIla, whether present in a
mixture with the other enantiomer (for example in a racemic mixture), or
substantially free of the other enantiomer.
As used in this specification, the terms alkyl, alkylene, alkenylene or
alkynylene include branched and unbranched groups. However, where specific
terms are used, for example propyl, isopropyl or propylene, these indicate
whether the group is branched or not. Diradicals, for example
2-oxo-piperazin-1,4-diyl, are numbered assuming that formula I is read
from right to left with the group A being at the right hand side, as
depicted in formula I hereinabove. Hence, for example,
2-oxo-piperazin-1,4-diyl signifies the group:
##STR12##
It will be appreciated that in this specification, the order of the two
numbers immediately preceding the term "diyl" in the name of a diradical
signifies the orientation of the diradical in a compound of formula I.
Thus the first number signifies the position in the diradical closest to
the group A. For example, the diradical represented by formula (d)
hereinbefore is named herein as a 4-oxoquinolon-3,7-diyl group whereas the
diradical represented by formula (i) is named herein as a
4-oxoquinolon-7,3-diyl group. Particular pharmaceutically acceptable salts
include, for example, salts with acids affording physiologically
acceptable anions, such as salts with mineral acids, for example a
hydrogen halide (such as hydrogen chloride and hydrogen bromide),
sulphulic acid or phosphoric acid, and salts with organic acids, for
example trifluoroacetic acid. Other pharimaceutically acceptable salts
include, for example salts with inorganic bases such as alkali metal and
alkaline earth metal salts (for example sodium salts), ammonium salts, and
salts with organic amines and quaternary bases forming physiologically
acceptable cations such as salts with methylamine, dimethylamine,
trimethylamine, ethylenediamine, piperiidine, morpholine, pyrrolidine,
piperazine, ethanolamine, triethanolamine, N-methylglucanmne,
tetramethylammonium hydroxide and benzyltiimethylammonium hydroxide. Many
of the compounds of formula I, and the pharmaceutically acceptable salt
and pro-drugs thereof, are novel, and accordingly are provided as one
aspect of the invention.
According to another aspect, the invention provides a process for preparing
a compound of general formula I, or a metabolically labile ester or amide
thereof, or a pharmaceutically acceptable salt thereof, which comprises
(A) For a compound of formula I in which n is 0 and M.sup.2 is NR.sup.3 or
--NR.sup.4 -D-NR.sup.5 --, reacting a compound of formula
Q.M.sup.2.H
or an acid addition salt thereof with a compound of formula
U.sup.1.L.A III
in which U.sup.1 is a leaving atom or group.
Examples of values for U.sup.1 include halogen, such as chlorine or
bromine, and hydrocarbylsulphonyloxy, such as methanesulphonyloxy and
p-toluenesulphonyloxy. When the group in L to which U.sup.1 is attached is
a carbonyl group, U.sup.1 may also represent a hydroxy group or a reactive
derivative thereof. Examples of reactive derivatives of a hydroxyl group
include acyloxy groups such as acetyloxy, and groups formed in situ by
reacting a compound of formula III in which U.sup.1 is hydroxy with a
peptide coupling reagent. Examples of peptide coupling reagents include
carbodiimides such as 1,3-dicyclohexylcarbodiiminde (DCC) preferably in
combination with 1-hydroxybenzotriazole hydrate (HOBT). Examples of acid
addition salts include, for example the hydrochlorides. The reaction may
conveniently be effected at a temperature in the range of from -10.degree.
to 120.degree. C., preferably from 10.degree. to 100.degree. C. Suitable
solvents include, for example, ethers such as tetrahydrofuran, amides such
as dimethylformamide, nitriles such as acetonitrile, halogenated
hydrocarbons such as dichloromethane and alcohols such as ethanol or
isopropanol. In some circumstances, for example when an acid addition salt
of a compound of formula II is used as starting material, or when the
compound of formula II is relatively unreactive, the reaction may
advantageously be performed in the presence of a base. Examples of
suitable bases include tertiary amines, such as triethylamine, and alkali
metal hydroxides, carbonates and bicarbonates, such as sodium or potassium
hydroxide, carbonate or bicarbonate. When the compound of formula II is
relatively unreactive a strong base such as an alkali metal hydride, for
example potassium hydride, may conveniently be used.
(B) For a compound of formula I in which A is carboxy, decomposing an ester
of formula
(M.sup.1).sub.n -Q-(M.sup.2).sub.1-n -L-COOR.sup.20 IV
in which R.sup.20 is a carboxyl protecting group. R.sup.20 may be any
conventional carboxyl protecting group that may be removed without
interfering with other parts of the molecule. Examples of carboxyl
protecting groups include (1-6C)alkyl groups (such as methyl, ethyl,
propyl or t-butyl), phenyl and benzyl, the phenyl moiety in any of which
may optionally bear 1 or 2 of halogeno, (1-4C)alkyl, (1-4C)alkoxy or
nitro.
The decomposition may be carried out using any one or more of the
conventional reagents and conditions known in the art for converting
carboxylic esters into carboxylic acids. Thus, for example, the
decomposition may conveniently be performed by base catalysed hydrolysis,
for example by using an alkali metal hydroxide such as lithium, potassium
or sodium hydroxide or an amine such as triethylamine, in the presence of
water. The base catalysed hydrolysis may conveniently be performed in the
presence of a solvent such as an alcohol, for example methanol or ethanol,
or an ether such as tetrahydrofuran or dioxan. Alternatively the
decomposition may be carried out by acid catalysed hydrolysis, for example
using aqueous acetic acid or trifluoroacetic acid. The temperature is
conveniently in the range of from -10.degree. to 100.degree. C., for
example from 10.degree. to 50.degree. C. When the alcohol residue is
t-butyl, this may also conveniently be removed by heating, for example at
a temperature in the range of from 80.degree. to 150.degree. C., alone or
in the presence of a suitable diluent such as diphenylether or
diphenylsulphone. A benzyl group may conveniently be removed by catalytic
hydrogenation, for example by hydrogenation in the presence of palladium
on carbon at a temperature in the range of from -10.degree. to 100.degree.
C. in the presence of a solvent such as an alcohol, for example methanol
or ethanol.
(C) For a compound of formula I in which L represents X.sup.1.Y.X.sup.2 and
Y is a group of formula (c), reacting a compound of formula
(M.sup.1).sub.n -Q-(M.sup.2).sub.1-n -X.sup.1.U.sup.2 V
in which U.sup.2 is a leaving atom or group, or an acid addition salt
thereof, with a compound of formula
H.Y.X.sup.2.A VI
or an acid addition salt thereof, in which X.sup.2 and A are as defined
hereinabove and Y is a group of formula (c) as defined hereinabove.
Examples of values for U.sup.2 include halogen, such as chlorine or
bromine, and hydrocarbylsulphonyloxy, such as methanesulphonyloxy and
p-toluenesulphonyloxy. When the group in X.sup.1 to which U.sup.2 is
attached is a carbonyl group, U.sup.2 may also represent a hydroxy group
or a reactive derivative thereof. Examples of reactive derivatives of a
hydroxyl group include acyloxy groups such as acetyloxy, and groups formed
in situ by reacting a compound of formula V in which U.sup.2 is hydroxy
with a peptide coupling reagent. Examples of peptide coupling reagents
include carbodiimides such as 1,3-dicyclohexylcarbodiimide (DCC),
preferably in combination with 1-hydroxybenzotriazole hydrate (HOBT).
Examples of acid addition salts include, for example the hydrochlorides.
The reaction may conveniently be effected at a temperature in the range of
from -10.degree. to 120.degree. C., preferably from 10.degree. to
100.degree. C. Suitable solvents include, for example, ethers such as
tetrahydrofuran, amides such as dimethylformamide, nitriles such as
acetonitrile, halogenated hydrocarbons such as dichloromethane and
alcohols such as ethanol. In some circumstances, for example when an acid
addition salt of a compound of formula VI is used as starting material,
the reaction may advantageously be performed in the presence of a base.
Examples of suitable bases include tertiary amines, such as triethylamine,
and alkali metal hydroxides, carbonates and bicarbonates, such as sodium
or potassium hydroxide, carbonate or bicarbonate.
(D) For a compound of formula I in which n is 0, reacting a compound of
formula
Q-U.sup.3 VII
in which U.sup.3 is a leaving atom or group, with a compound of formula
HM.sup.2.L.A VIII
or an acid addition salt thereof, in which L and A are as defined
hereinabove. Examples of values for U.sup.3 include halogen, such as
chlorine or bromine, and cyano. Examples of acid addition salts include,
for example the hydrochlorides. The reaction may conveniently be effected
at a temperature in the range of from -10.degree. to 120.degree. C.,
preferably from 10.degree. to 100.degree. C. Suitable solvents include,
for example, ethers such as tetrahydrofuran and dioxan, amides such as
dimethylformamide, nitriles such as acetonitrile, halogenated hydrocarbons
such as dichloromethane, alcohols such as ethanol and water.
In some circumstances, for example when an acid addition salt of a compound
of formula VIII is used as starting material, the reaction may
advantageously be performed in the presence of a base. Examples of
suitable bases include tertiary amines, such as triethylamine, and alkali
metal hydroxides, carbonates and bicarbonates, such as sodium or potassium
hydroxide, carbonate or bicarbonate.
(E) For a compound of formula I in which L is X.sup.1.Y.X.sup.2 and X.sup.1
comprises a CONH group, reacting the appropriate carboxylic acid of
formula
(M.sup.1).sub.n -Q-(M.sup.2).sub.1-n -X.sup.1a IX
in which X.sup.1a is a residue of a carboxylic acid group, or a reactive
derivative thereof, with the appropriate amine of formula
X.sup.1b.Y.X.sup.2.A X
in which X.sup.1b is a residue of an amine group.
Examples of values for X.sup.1a are (1-2C)alkyleneCOOH,
benzyl(1-2C)alkyleneCOOH and COOH. Examples of values for X.sup.1b are
H.sub.2 N and H.sub.2 N(1-3C)alkylene.
Examples of reactive derivatives of the compounds of formula IX include
acyl halides such as the chlorides and bromides, and groups formed in situ
by reacting a residue of a carboxylic acid with a peptide coupling
reagent, such as carbodimide, for example 1,3-dicyclohexylcarbodimide,
preferably in combination with1-hydroxybenzotriazole hydrate (HOBT).
The reaction is conveniently performed at a temperature in the range of
from 0.degree. to 100.degree. C. Suitable solvents include halogenated
hydrocarbon such as methylene chloride, amide, such as dimethylformamide
and tertiary amines such as triethylamine.
(F) For a compound of formula I in which L is X.sup.1.Y.X.sup.2 and X.sup.1
is (2-4C)alkenylene, reactinog a compound of formula
(M.sup.1).sub.n -Q-(M.sup.2).sub.1-n -X.sup.1c XI
in which X.sup.1c is an appropriate aldehyde-containing group with the
appropriate Wittig reagent of formula
X.sup.1d.Y.X.sup.2.A XII
in which X.sup.1d is a triarylphosphonylalkylene group such as
triphenylphosphinylmethylene.
The reaction is conveniently performed at a temperature in the range of
from -20.degree. to 50.degree. C., preferably from 0.degree. to 25.degree.
C. Convenient solvents include ethers such as tetrahydrofuran, sulphoxides
such as dimethylsulphoxide and aromatic hydrocarbons such as toluene.
(G) For a compound of formula I in which L is X.sup.1.Y.X.sup.2 and X.sup.1
comprises an oxy (ether) link, reacting the appropriate compound of
formula
(M.sup.1).sub.n -Q-(M.sup.2).sub.1-n -X.sup.1c XIII
with the appropriate compound of formula
X.sup.1f.Y.X.sup.2 A XIV
in which one of X.sup.1e and X.sup.1f is a residue of an alcohol group, and
the other is a residue of an alcohol group or a group containing a leaving
atom or group.
When X.sup.1e and X.sup.1f both represent residues of alcohol groups, the
reaction may conveniently be effected in the presence of a dehydrating
agent such as diethyl azodicarboxylate-triphenylphosphinc. Suitable
solvents for the reaction include ethers such as tetrahydrofuran, and
amides such as dimethylformamide. The reaction is conveniently effected at
a temperature in the range of from 0.degree. to 50.degree. C.
(H) For a compound of formula I in which X.sup.2 is CH.sub.2 CH(NHXR.sup.6)
reacting a compound of formula
(M.sup.1).sub.n -Q-(M.sup.2).sub.1-n -X.sup.1 -Y-X.sup.2a A XV
in which X.sup.2a is CH.sub.2 CH(NH.sub.2), or an acid addition salt
thereof, with a compound of formula
R.sup.6.X.U.sup.4 XVI
in which U.sup.4 is a leaving atom or group.
Examples of values for U.sup.4 include halogen, such as chlorine or
bromine. Examples of acid addition salt include for example, the
hydrochloride. The reaction may conveniently be effected at a temperature
in the range of from -10.degree. to 120.degree. C. preferably from
10.degree. to 100.degree. C. Suitable solvents include for example ethers
such as tetrahydrofuran, amides such as dimethylformamide, nitriles such
as acetonitrile, halogenated hydrocarbon such as dichloromethane and
alcohols such as ethanol. The reaction is conveniently performed in the
presence of a base, for example a tertiary amine such as triethylamine.
(I) For a compound of formula I in which L is X.sup.1.Y.X.sup.2 and X.sup.2
represents oxyalkylene or oxyalkenylene, reacting a compound of formula
(M.sup.1).sub.n -Q-(M.sup.2).sub.1-n -X.sup.1 -Y-X.sup.2c XVIII
with the appropriate compound of formula
X.sup.2d -A XIX
in which X.sup.2c is a hydroxy group, or a reactive derivative thereof
(such as a halide), and X.sup.2d is a hydroxyalkylene or hydroxyalkenylene
group, or a reactive derivative thereof (such as a halide, for example a
bromide).
The reaction is conveniently performed in the presence of a strong base,
such as an alkali metal hydride, for example, sodium hydride. Suitable
solvents include amides, such as dimethylformamide. The reaction is
conveniently performed at a temperature in the range of from 0.degree. to
1 00C.
(J) For a compound of formula I in which L is X.sup.1.Y.X.sup.2 and X.sup.2
represents CONHalkylene, reacting a compound of formula
(M.sup.1).sub.n -Q-(M.sup.2).sub.1-n -X.sup.1 -Y-X.sup.2e XX
with the appropriate compound of formula
X.sup.2f -A XXI
in which X.sup.2e represents a carboxyl group or a reactive derivative
thereof (such as an acyl halide, for example an acyl chloride, or
anhydride) and X.sup.2f represents an aminoalkylene group, or an acid
addition salt thereof (such as a hydrochloride).
Suitable solvents include tertiary amines such as triethylamine halogenated
hydrocarbons such as methylene chloride and amides such as
dimethylformamide. The reaction is conveniently performed at a temperature
in the range of from 0.degree. to 100.degree. C.
(K) For a compound of formula I in which L is X.sup.1.Y.X.sup.2 and X.sup.1
represents CONH or CONHalkylene, reacting a compound of formula II with a
compound of formula
OCN-X.sup.1g -Y-X.sup.2 -A XXII
in which X.sup.1g is a bond or an alkylene group.
The reaction is conveniently performed at a temperature in the range of
from 0.degree. to 100.degree. C. Suitable solvents include halogenated
hydrocarbons, such as dichloromethane.
(L) For a compound of formula I in which L is X.sup.1 -Y-X.sup.2 and A is
NHSO.sub.2 R.sup.10, reacting a compound of formula
(M.sup.1).sub.n -Q-(M.sup.2).sub.1-n -X.sup.1 -Y-X.sup.2 -NH.sub.2 XXIV
with a compound of formula
R.sup.10 SO.sub.2 U.sup.5 XXV
in which U.sup.5 is a leaving atom or group, such as a halogen atom, for
example a chlorine atom.
The reaction is conveniently performed in the presence of a base such as a
tertiary amine, for example triethylamine, and at a temperature in the
range of from -10.degree. to 40.degree. C. Suitable solvents include
amides such as dimethylformamide and halogenated hydrocarbons such as
dichloromethane.
(M) For a compound of formula I in which L is X.sup.1.Y.X.sup.2 and X.sup.1
is (1-2C)alkylenecarbonyloxy, reacting a compound of formula
(M.sup.1).sub.n -Q-(M.sup.2).sub.1-n -X.sup.1k XXVI
in which X.sup.1k represents (1-2C)alkylenecarboxy or a reactive derivative
thereof, with a compound of formula
HO-Y-X.sup.2 -A XXVII
The reaction is conveniently performed at a temperature in the range of
from 0.degree. to 100.degree. C. Suitable solvents include halogenated
hydrocarbons such as dichloromethane.
(N) For a compound of formula I in which L represents X.sup.1.Y.X.sup.2,
X.sup.1 represents (1-3C)alkylenecarbonyl and Y represents a phenylene
group of formula (a), reacting a compound of formula
(M.sup.1).sub.n -Q-(M.sup.2).sub.1-n -X.sup.11 XXVIII
in which X.sup.11 represents a (1-3C)alkylenecarboxyl group, or a reactive
derivative thereof, with a compound of formula VI in the presence of a
Lewis acid.
Example of suitable Lewis acids include aluminium trichloride. Examples of
reactive derivatives of compounds of formula XXVIII include the halides,
such as the chlorides.
The reaction is conveniently performed at a temperature in the range of
from -10.degree. to 50.degree. C. Suitable solvents include halogenated
hydrocarbons, such as dichloromethane.
(O) For a compound of formula I in which L represents X.sup.1.Y.X.sup.2 and
X.sup.2 represents NR.sup.21 CO(1-2C)alkylene, reacting a compound of
formula
(M.sup.1).sub.n -Q-(M.sup.2).sub.1-n -X.sup.1 -Y-NHR.sup.21 XXX
with a compound of formula
X.sup.2h -A XXX
in which X.sup.2h represents a carboxy(1-2C)alkyl group, or a reactive
derivative thereof.
Examples of reactive derivatives of compounds of formula XXX include
halides, such as chlorides, and anhydrides.
The reaction is conveniently performed at a temperature in the range of
from 0.degree. to 100.degree. C. Suitable solvents include amides such as
dimethylformamide.
Certain compounds of formula I may be converted into other compounds of
formula I using conventional methods. For example, a compound of formula I
in which L represents X.sup.1.Y.X.sup.2.A in which X.sup.1 is a
(2-4C)alkylene group may be prepared by hydrogenating a corresponding
compound of formula I in which X.sup.1 represents a (2-4C)alkenylene
group. The hydrogenation may be effected, for example, in the presence of
palladium on charcoal and in a suitable solvent such as an alcohol, for
example ethanol. A compound of formula I in which L represents
X.sup.1.Y.X.sup.2.A in which X.sup.1 is (1-3C)alkyleneCH(OH) may be
prepared by reducing a corresponding compound of formula I in which
X.sup.1 is (1-3C)alkylenecarbonyl. The reduction may be effected, for
example, using an alkali metal borohydride such as sodium borohydride.
The intermediates used in the aforementioned processes are known or may be
prepared by methods analogous to those known for the preparation of known
compounds.
Thus, the compounds of formula IV may be prepared by methods analogous to
processes (A) and (C) to (H) herein, but starting from the appropriately
protected starting materials. It will be appreciated that some compounds
of formula IV are compounds according to the invention.
The compounds of formula II in which n is 0 and M.sup.2 is a
2-oxopiperazin-1,4-diyl group may be prepared by reacting piperazinone
with a compound of formula VII. The compounds of formula XV may be
prepared by deprotecting a corresponding compound of formula:
(M.sup.1).sub.n -Q-(M.sup.2).sub.1-n -X.sup.1 -Y-X.sup.2b.A XVII
wherein X.sup.2b is CH.sub.2 CH(NHR.sup.11) and R.sup.11 is an amine
protecting group.
Examples of amine protecting groups include oxycarbonyl groups such as
benzyloxycarbonyl. A benzyloxycarbonyl group may conveniently be removed,
for example, by hydrogenation in the presence of a catalyst such as
palladium on charcoal.
The compounds of formula XVII may be prepared by a method analogous to the
preparation of a compound of formula I, but starting from the appropriate
starting material. For example, if a compound of formula XVII in which
X.sup.1 is methyleneoxy and Y is phenylene, is desired this may be
prepared by a method analogous to process (G) herein, starting with a
compound of formula XIII and the appropriate N-protected derivative of
tyrosine.
The compounds of formula XVIII may be prepared by reacting a compound of
formula VII with a compound of formula
H-X.sup.1 -Y-X.sup.2g XXIII
in which X.sup.2g is a hydroxy group or a protected derivative thereof (for
example a methoxy group), followed if necessary by the removal of any
protecting group, (for example by treatment with hydrobromic acid) and, if
desired, conversion of the hydroxy group into a reactive derivative
thereof by a known method.
Many of the intermediates, for example compounds of formulae XV and XVII,
and the compounds of formula II and VIII in which M.sup.2 is
2-oxopiperazin-1,4-diyl are novel and form further aspects of this
invention.
The compounds of formula I may be converted into pharmaceutically
acceptable salts and/or metabolically labile esters or amides thereof by
methods well known in the art. For example, a pharmaceutically acceptable
salt may be formed by reacting a compound of formula I with an acid
capable of affording a physiologically acceptable anion, or a base capable
of affording a physiologically acceptable cation. A pharmaceutically
acceptable metabolically labile ester or amide may be formed respectively
by esterifying a compound of formula I using a conventional technique, or
reacting an acid, or a reactive derivative thereof with the appropriate
amine.
The ability of the compounds of formula I to inhibit platelet aggregation
may be demonstrated using a standard test (a) based on that described by
Born (Nature, 1962, 194, 927-929) and involving:
(i) aggregating human, citrated, platelet-rich plasma by addition of
adenosine diphosphate so as to generate a dose-response curve;
(ii) generating a dose-response curve for ADP stimulated platelet
aggregation in the presence of increasing amounts of a test compound
(generally in the range 10-.sup.5 M to 10-.sup.10 M); and
(iii) calculating a pA.sub.2 value indicating potency of platelet
aggregation inhibition for the test compound, averaged over several
concentrations, from the calculated 50% response value for ADP aggregation
in the presence and absence of the test compound.
Test (a) may be modified so as to assess the effects of a test compound ex
vivo on the aggregation of human blood platelets after administration of
the test compound to a laboratory animal, such as a rat, rabbit, guinea
pig, mouse or dog. For example, groups of four male, fasted Alderley Park
Wistar rats are orally dosed with a test compound or appropriate vehicle,
and at suitable time intervals (1,3,5 and 8 hours after dosing) animals
are anaesthetised with fluothane and bled by heart puncture. Blood is
collected into 3.2% citrate (1 part to 9 parts whole blood) and platelet
poor plasma (ppp) prepared by centrifugation (4500.times.g for 10 min).
Human blood is collected into 3.2% trisodium citrate (1 part to 9 parts
whole blood) and centrifugated (200.times.g for 15 min) to produce
platelet rich plasma (prp).
Equal volumes (125 .mu.l) of rat ppp and human prp are mixed together, ADP
added, and the whole incubated (37.degree. C.) and stirred (900 rpm) in a
BioData platelet aggregometer. Aggregation is induced with ADP and agonist
EC.sub.50 values calculated for human prp/rat ppp mixtures from animals
dosed with test compound or vehicle. A mean concentration ratio
(concentration of ADP required to cause a 50% aggregation response in
human prp/rat ppp mixtures from animals dosed with antagonist, divided by
the concentration of ADP to cause 50% aggregation in human prp/rat ppp
mixtures from animals dosed with vehicle) is calculated at each time
point.
The ability of the compounds of formula I to inhibit binding of fibrinogen
to GPllb-Illa may be demonstrated using the following standard test (b)
involving:
(i) Preparation of human platelet lysates.
Platelet rich plasma (PRP) is harvested by centrifugation (1000 rpm, 15
mins) of whole blood anticoaoulated with acid citrate dextrose (trisodium
citrate 85 mM, citric acid 70 mM, d-glucose 110 mM) 1 part to 6 parts
blood. Prostacyclin (PGI.sub.2, 1 .mu.M) is added to the PRP before
centrifugation (2400 pm, 15 mins) and the resulting pellet is resuspended
in modified Tyrodes' solution (NaCl 130 mM, KCl 26 mM, NaHCO.sub.3 12 mM,
NaH.sub.2 PO.sub.4 0.5 mM, MgCl.sub.2 1 mM, CaCl.sub.2 20 mM, Glucose 12
mM, HEPES 5 mM) containing bovine serum albumin 3.5 g/L, PGI2 1 .mu.M and
hirudin 0.5 U/ml. The platelet suspension is centrifuged (2400 rpm, 15
mins) and the resultant pellet resuspended in 500 .mu.l of lysis buffer
(octyl glucoside 50 mM, HEPES 10 mM, NaCl 150 mM, CaCl.sub.2 1 mM,
MgCl.sub.2 1 mM, PMSF 1 mM, NEM 10 mM, leupeptin 0.1 mM), agitated at
4.degree. C. for 15 minutes then centrifuged at 24000 rpm, 15 mins. The
supernatant is stored at 4.degree. C. and the pellet re-suspended in 500
.mu.l of lysis buffer. The centrifugation process is repeated a further 3
tlimes, the pooled supernatants being stored at -70.degree. C.
(ii) Receptor purification.
GP Ilb/Ila is isolated from human platelet lysates using a 2 ml peptide
(KYGRGDS) coupled CNBr activated Sepharose affinity column. A 1.5 ml
volume of platelet lysate is placed on the column and allowed to stand
overnight at 4.degree. C. Buffer (30 mls, octyl gluicoside 25 mM, HEPES 10
mM, NaCl 150 mM, CaCl2 1 mM, MgCl2 1 mM, PMSF 1 mM, NEM 10 mM, leupeptin
0.1 mM) is passed through the column and 2 ml fractions are collected
throughout. GPIIb/IIIa is eluted with 12 mls of buffer containing
HHLGGAKQAGDV (2 mg/ml, pH 7.5), the column is washed using 4 mls buffer
and the remaining GPIIb/IIIa eluted using 12 mls buffer containing GRGDSPG
(1 mg/ml pH 7.5). The column is finally washed using 20 mls of buffer and
can be used for up to three such preparations. Fractions containing
FGPIIb/IIIa are identified using gel electrophoresis and immunoblotting,
pooled and stored at -70.degree. C.
(iii) GPIIb/IIIa ELISA
96 well microtitre plates are coated with 100 .mu.l purified human platelet
fibrinogen receptor (GPIIb/IIIa) diluted in coating buffer (Tris-HCl 20
mM, NaCl 150 mM, CaCl.sub.2 1 mM, pH 7.4) and left overnight at 4.degree.
C. The plates are washed using washing buffer (Tris-HCl 50 mM, NaCl 100
mM, CaCl.sub.2 2 mM, pH 7.4) and non-specific binding, blocked by the
addition of 200 .mu.l 2% BSA (2 hours, 30.degree. C.). The plates are
washed prior to incubation (2 hours, 30.degree. C.) with 100 .mu.l
biotinylated fibrinogen (10 nm) containing either vehicle or test
compound. The plates are washed, incubated with streptavidin (5 .mu.g/ml,
1 hour, ambient temperature), then washed again before the addition of 100
.mu.l biotinylated horse radish peroxidase (0.1 .mu.g/ml, 1 hour, ambient
temperature). The plates are then washed and equal volumes of peroxidase
substrate (3, 5, tetramethyl benzidine 0.4 g/l) and H.sub.2 O.sub.2
(0.02%) are mixed together immediately before addition of 150 .mu.l to
each well. Colour is allowed to develop for 10-15 mins before optical
densities are read at 650 nM.
______________________________________
Abbreviations
______________________________________
PMSF Phenylmethylsulphonylfluoride
HEPES (N-2-Hydroxyethyl!piperazine-N-2-ethanesulphonic acid!
NEM N-ethyl maleimide
______________________________________
The concentration of compound required to cause 50% inhibition of
biotinylated fibrinogen binding, is calculated and expressed as a
pIC.sub.50 (-log(IC.sub.50)).
In general, test compounds shiowing activity in this test show a pIC.sub.50
of greater than about 4.0.
The effects of each of the compounds of formula I exemplified herein in the
above tests are gyiven in the table below. Where a range of values is
given, the compound has been tested more than once. A dash (--) signifies
that a compound has not been tested.
______________________________________
TABLE OF BIOLOGICAL TEST RESULTS
Example Test (a)
Test (b)
______________________________________
1 6.5-6.8 5.8-6.4
2 7.1-7.3 7.6
3 6.3 6.6
4 8.9 9.1
5 6.0 6.0
6 7.2 7.6
7 6.3 5.2-5.4
8 6.5 7.1
9 4.9 4.3
10 5.7 6.0
11 5.7 4.4
12 6.3 7.2
13 5.3 4.4-4.8
14 5.1 <4
15 5.6 5.9
16 6.8 6.7
17 7.4 7.7
18 6.3 6.5
19 5.6 5.7
20 5.3 4.8
21 6.8-7.2 6.3-6.8
22 6.7-6.9 5.4
23 6.0 4.5-5.2
24 5.7 4.5
25 5.1 4.8
26 5.8 6.2
27 5.1 5.6
28 4.7 5.7
29 -- --
30 5.3 5.9
31 -- --
32 6.7 7.3
33 6.4 6.9
34 8.7 8.7
35 6.4 7.2
36 8.7 9.0
37 5.6 6.7
38 7.5 8.7
39 4.6 6.6
40 7.1 7.7
41 <4 <4
42 4.3 5.2
43 4.4 5.5
44 5 7
45 5.4 6.1
46 6 7.6
47 5.2 4.4
48 5.0 6.6
49 7.1 8.2
50 6.0-6.1 <4
51 7-7.9 7.6-8.4
52 5 <4
53 5.8 5.9
54 4.8 <4
55 4.5 4.8
56 5.5 4.8
57 7.6 7.6
58 5.5 4.4
59 7.2 7.5
60 5 4.8
61 7.5 6.7
62 7.9-8.6 8.1
63 6.9 6.5
64 7.5 7.7
65 5.2 5.6
66 5.7 6.6
67 8.6 8.5
68 6.5 7.9
69 4.9 5.4
70 7.1 7.8
71 4.9 4.4
72 6.3 4.4
73 6.3 7.2
74 5 5.7
75 4.5 5.4
76 4.5 5.9
77 5.1 6.3
78 6.8 6.6
79 7.9 8.5
80 6.6 6.4
81 4.8 6.7
82 6.3 7.9
83 4.4 5.7
84 7.2 7.7
85 5.8 6.6
86 5.4 6.7
87 5.6 7.2
88 9 8.6
89 7.4 8.7
90 8 8.5
91 6.8 6.7
92 5.7 7.1
93 7.9 8.5
94 6.5 8.6
95 5 5.1
96 7.1 8.4
97 5.4 5.5
98 7.6 8.5
99 5.4 6.6
100 4.4 5.4
101 6.3 7.5
102 5.7 5.8
103 4.5 5.1
104 <4 4.7
105 6.6 6.6
106 4.8 4.4
107 4.5 <4
108 6.3 5.9
109 6.5 6.2
110 5.2 <4
111 5.3 5.2
112 5.2 5.5
113 <4 4.6
114 <4 5.6
115 5.4 <4
116 5.7 5.6
117 4.9 5.4
118 6.7 6.4
119 4.5 <4
120 5.4 4.3
121 5.9 5.4
122 6.2 5.4
123 6.0 7.0
124 6.1 6.6
125 6.8 7.8
126 4.8 5.5
127 5.8 6.7
128 6.8 6.3
129 7.9 6.5
130 <4 5.4
131 4.6 4.5
132 4.2 4.5
133 5.7 4.5
134 4.8 4.6
135 4.5 <4
136 6.9 5.6
137 7.2 5.5
138 5 4.9
139 6.6 5.4
140 5.8 6.3
141 4.5 4.5
142 5.3 5.3
143 5.0 4.5
144 5.3 5.3
145 5.5 5.3
146 5.1 5.2
147 6.4 6.2
148 7.3 7.5
149 4.7 4.7
150 6.5 6.5
151 6.2 5.4
152 7.0 7.0
153 4.8 4.3
154 5.0 5.6
155 5.5 <4
156 4.7 5.8
157 6.5 7.1
158 6.2 7.0
159 6.3 5.7
160 6.1 7.8
161 4.9 4.3
162 4.7 6.2
163 6.4 6.6
164 8.1 7.2-7.4
165 5.9 4.7
166 5.8 6.5
167 6.6 6.7
168 6.1 6.4
169 4.4 5.0
170 4.8 <4
171 5.2 <4
172 5.2 4.3
173 5.9 6.7
174 6.4-6.8 8.0-8.3
175 5.9 6.2
176 6.7 8.0
177 5.8 4.1
178 5.5 6.0
179 4.8 5.4
180 5.5 --
181 6.5 --
182 5.1 4.7
183 4.5 <4
184 5.3 <4
185 5.4 4.8
186 5.3 5.9
187 4.8 --
188 6.0 --
189 5.9 6.5
190 4.2 4.7
191 <4 5.4
192 <4 6.6
193 4.4 6.6
194 5.4 6.9
195 5.6 6.8
196 4.0 5.2
197 4.2 4.8
198 6.1 7.7
199 6.3 --
200 7.9 8.4
201 4.3 <4
202 -- --
203 7.2 8
204 7.1 8.9
205 6.6 --
206 6.6 8.0
207 6.5 6
208 6.5 --
209 6.7 --
210 6.5 --
211 5.8 6.8
212 7.1 --
213 6.7 6.3
214 -- --
215 6.9 --
216 5.7 --
217 6.5 --
218 6.0 --
219 7.5 --
220 5.5 --
221 6.8 --
222 6.5 5.6
223 6.0 5.8
224 4.5 6.3
225 6.8 --
226 4.7 5.5
227 5.6 7.0
228 5.0 <4
229 5.4 7.1
230 5.0 5.3
231 6.7 7.5
232 4.5 --
233 5.2 6.3
234 6.2 6.7
235 5.2 6.7
236 6.1 --
237 6.1 7.5
238 5.9 --
239 5.6 --
240 7.6 --
241 8.2 --
242 6.5 --
243 8.0 --
______________________________________
In general, it has been found that compounds of formula I in which A is
carboxy show a higher level of activity in test (a), and test (b) than
those in which A is an ester group. However, the compounds in which A is
an ester group have often been found to show a higher level of activity
than those where A is carboxy in test (a) when the test is modified to
assess the activity of test compounds on oral administration. For example,
the compound described in Example 1 hereinafter has been found to give a
pA.sub.2 of 6.5-6.8 in test (a) and a pIC.sub.50 of 5.8-6.4 in test (b),
whereas the compound of Example 2 has been found to give a pA.sub.2 of
7.1-7.3 in test (a) and a pIC.sub.50 of 7.6 in test (b). However, the
compound of Example 1 has been found to be active for up to 12 hours when
dosed orally to dogs at 5 mg/kg. Without wishing to be bound by theory it
is accordingly believed that the compounds of formula I in which A
represents an ester group function as pro-drugs for compounds of formula I
in which A is a carboxyl group.
As stated previously, the compounds of formula I may be used in the therapy
or prevention of diseases in which cell adhesion (especially platelet
aggregation) is involved, for example thrombosis (e.g. stroke and
thrombotic events accompanying unstable angina and transient ischaenic
attack), myocardial infarction, atherosclerosis, thromboembolism and
reoceilusion during and after thrombolytic therapy. The compounds may also
be useful for the prevention of reocciusion and restenosis following
percutanieous transluminal coronary angioplasty (PTCA) and coronary artery
bypass graft. It will also be appreciated that the compounds may be useful
in the treatment of other diseases mediated by binding of adhesion
molecules to GPIIb/IIIa, for example cancer.
According to another aspect, therefore, the invention provides a method of
inhibiting platelet aggregation in a warm-blooded mammal requiring such
treatment, which comprises administering an effective amount of a compound
of formula I, or a pharmaceutically acceptable salt or pro-drug thereof.
According to yet another aspect, the invention provides a method of
inhibiting binding of fibrinogen to GPIIb/IIIa in a warm-blooded animal
requiring such treatment, which comprises administering an effective
amount of a compound of formula I, or a phamaceutically acceptable salt or
pro-drug thereof.
According to a further aspect, the invention provides the use of a compound
of formula I or a pharmaceutically acceptable salt or pro-drug thereof for
the manufacture of a medicament for the prevention or treatment of a
disease involving platelet aggregation.
According to yet another aspect, the invention provides the use of a
compound of formula I or a pharmaceutically acceptable salt or pro-drug
thereof, for the manufacture of a medicament for the prevention or
treatment of a disease involving binding of fibrinogen to GPIIb/IIIa.
In general, a compound of formula I will be administered for this purpose
by an oral, rectal, topical, intravenous, subcutaneous, intramuscular or
inhalation route, so that a dose in the range of from 0.01 to 50 mg/kg
body weight will be given, depending upon the route of administration, the
age and sex of the patient, and the severity of the condition to be
treated.
The compounds of formula I will generally be used in the form of a
pharmaceutical composition comprising a compounid of formula I or a
pharmaceutically acceptable salt thereof as defined hereinabove, together
with a pharmaceutically acceptable diluent or carrier. Such a composition
is provided as a further feature of the invention and may be in a variety
of dosage forms. For example, it may be in the form of tablets, capsules,
solutions or suspensions for oral administration; in the form of cream or
ointments or a transdermal (skin) patch for topical administration; in the
form of a suppository for rectal administration; in the form of a sterile
solution or suspension for administration by intravenous or intramuscular
injection; in the form of an aerosol or a nebuliser solution or
suspension, for administration by inhalation; and in the form of a powder,
together with pharmaceutically acceptable inert solid diltients such as
lactose, for administration by insufflation. Depending upon the route of
administration, the composition may comprise, for example, from 0.1 to
99.9% by weight of a compound of formula I.
The pharmaceutical compositions may be obtained by conventional procedures
using pharmaceutically acceptable diluents and carriers well known in the
art. Tablets and capsules for oral administration may conveniently be
formed with an enteric coating, for example comprising cellulose acetate
phthalate, to minimise contact of the active ingredient of formula I with
stomach acids.
The compounds according to the invention may be co-adminstrated or
co-formulated with one or more agents known to be of value in diseases or
conditions intended to be treated; for example a known platelet
aggregation inhibitor (e.g. aspirin, a thromboxane antagonist or a
thromboxane synthase inhibitor), hypolipidemic agent, anti-hypertensive
agent, thrombolytic agent (such as streptokinase, urokinase, prourokinase,
tissue plasminogen activator and derivatives thereof), beta-adrenergic
blocker or a vasodilator may usefully also be present in a pharmaceutical
composition of the invention for use in treating a heart or vasecular
disease or condition.
In addition to their use in therapeutic medicine, the compounds of formula
I are also useful as pharmacological tools in the development and
standardisation of test systems for the evaluation of the effects of
adhesion molecules in laboratory animals such as cats, dogs, rabbits,
monkeys, rats and mice, as part of the search for new therapeutic agents.
The compounds of formula I may also be used because of their platelet
aggregation inhibitory properties in helping to store blood and to
maintain the viability of blood and blood vessels in warm-blooded animals
(or parts thereof) under-going artificial extracorporeal circulation, for
example during limb or organ transplants. When used for this purpose a
compound of formula I, or a physiologically acceptable salt thereof, will
generally be administered so that a steady state concentration in the
range, for example, 0.1 to 10 mg. per litre is achieved in the blood.
As a further aspect of the present invention we provide the novel optically
active compound
(-)-(3R)-3-methyl-4-{4-4-(4-pyridyl)piperazin-1-yl!phenoxy}butyric acid,
hereinafter (-)-(3R)! and pharmaceutically-acceptable salts, esters,
amides or solvates thereof. The optically active (-)-(3R) compound of
Example 246 is an optical isomer of the racemic mixture
(3RS)-3-methyl-4-{4-4-(4-pyridyl)piperazin-1-yl!phenoxy}butyric acid of
Example 203).
Organic compounds can exist in optically active forms. Such compounds
possess the property of being able to rotate the plane of plane-polarised
ligYht in either a dextrorotary prefix (+)! or laevorotary prefix (-)!
manner. Typically an optically active compound possesses an asymmetric or
chiral atom such as a tetrahedral carbon atom which is bonded to four
different atoms or groups. The four different atoms or groups can be
arranged around the asymmetric carbon atom in two ways to give two chiral
compounds which are structurally related as mirror images of one another.
Such compounds are termed stereoisomers or enantiomers. Enantiomers have
identical physical and chemical properties except that they rotate the
plane of plane-polarised light by an equal amount but in opposite
directions. A racemic mixture is a mixture of equal amounts of a pair of
enantiomers. Such a mixture does not cause rotation of the plane of
plane-polarised light.
The stereochemical purity of an organic compound can be of importance in
the fields of pharmaceutical chemistry and pharmacology. Many
macromolecules such as the enzymes and receptors within warm-blooded
animals which are involved in the maintenance of life are built up from
chiral building blocks such as the chiral amino acids. The individual
enantiomers which together make up a racemic mixture of a
pharmacologically active compound may interact to differing extents with a
chiral macromolecule such as an enzyme or receptor. The individual
enantiomers may therefore possess different potencies as enzyme inhibitors
or receptor antagonists. In addition the rate and extent of the
absorption, distribution, metabolism and excretion observed when one
enantiomer is dosed to a warm-blooded animal may differ from that observed
when the mirror image form is so dosed, i.e. the enantiomers may possess
different pharmacokinetic properties.
Furthermore the stereochemical purity of an organic compound may also be of
importance to the nature and extent of the side effects which may be
obtained when a pharmacologically-active compound is dosed. Thus one
enantiomer may be a useful compound whereas the other enantiomer may give
rise to deleterious side effects or toxicity. It has, for example, been
suggested that one of the enantiomers of thalidomide was a safe and
effective sedative whereas the other enantiomer controlled the racemnic
mixture's teratogenic side effect.
As a possible aid in the search for compounds with an improved therapeutic
ratio, it would be desirable to find a compound with increased potency
over the compounds such as that of Example 203.
It is also known that there are several classes of adhesion molecules such
as the integrins, selectins and cadherins. Integrins are found on
leucocytes and platelets and selectins are found on leucocytes and
endothelial cells. Within each class of adhesion molecules there are many
members. The integrin family includes, for example, GPIIb/IIIa which binds
fibrinogen, the integrin .alpha..sub.v .beta..sub.3 which binds
vitronectin and the integrin .alpha..sub.5 .beta..sub.1 which binds
fibronectin. It is believed that the more useful therapeutic platelet
aggregation inhibitors will possess selectivity of inhibitory effect
between classes of adhesion molecules and between family members of each
class of adhesion molecules. Thus it would also be desirable to find a
compound which possesses this selectivity or which possesses greater
selectivity than known platelet aggregation inhibitors.
Furthermore it is known that there are several classes of GPIIb/IIIa
antagonists. For example, monoclonal antibody antagoniists to GPIIb/IIIa
have been raised. In addition, small molecules which inhibit the binding
of adhesion molecules to GPIIb/IIIa are also known, for example from U.S.
Pat. Nos. 5,039,805 and 5,084,446, from Canadian Patent Application Nos.
2,008,161, 2,037,153 and 2,061,661, and from Alig et ali, J. Med. Chem.,
1992, 35, 4393. Commonly the structures of these compounds are based upon
the binding regions of the adhesion molecules, for example the amino acid
sequence RGD (arginyl glycyl aspartate) within the structure of
fibrinogen. It is believed that such compounds can be used to inhibit
platelet aggregation and, for example, thrombus formation for sufficient
time to allow healing of damaged tissue without the deleterious sequelae
of over-robust platelet aggregation processes. It is a theoretical concern
relating to the various classes of GPIIb/IIIa antagonists that the
inhibition of platelet aggregation may lead to a decrease in the rate of
blood clotting and hence an increase in bleeding events and times.
Although a small increase in bleeding times may be acceptable, certain
clinically relevant bleeding events such as intracranial haemorrhage could
be life-threatening.
Thus it would be desirable to find a compound with the advantage of the
potent GPIIb/IIIa antagonist activity disclosed for the compound of
Example 203 which did not possess, or which possessed to a lesser decree,
the disadvantages of increased bleeding, times and/or deleterious
clinically relevant bleeding, events associated with the known GPIIb/IIIa
antagonists.
According, to the present invention there is provided the optically active
compound (-)-(3R)-3-methyl-4-
{4-4-(4-pyridyl)piperazin-1-yl!phenoxy}butyric acid, or a
pharmaceutically-acceptable salt, ester, amide or solvate thereof,
substantially free of the (+)-(3S) stereoisomer.
Thc (-)-(3R) compound possesses substantially better potency as a
GPIIb/IIIa antagonist than the corresponding (+)-(3S) isomer (greater than
10-fold more potent). The (-)-(3R) compound also possesses selectivity of
inhibitory effect between classes of adhesion molecules and between family
members of those classes. For example, the compound possesses activity
against the binding of GPIIb/IIIa to fibrinogen (pIC.sub.50 =7.65) but not
the binding of .alpha..sub.v .beta..sub.3 to vitronectin (pIC.sub.50 less
than 4) or the binding of .alpha..sub.v .beta..sub.1 to fibronectin
(pIC.sub.50 less than 4).
Accordingly the (-)-(3R) compound is a novel, potent and selective
fibrinogen receptors antagonist that substantially reduces the liability
or possibility of obtaining adverse effects such as excessive bleeding
associated with the administration of other fibrinogen receptor
antagonists such as the (3RS)-racemic mixture. Use of the (-)-(3R)
compound also eliminates the liability or possibility of obtaining adverse
effects associated with the administration of the therapeutically less
effective (+)-(3S) compound which is a constituent of the (3RS)-racemic
mixture. Use of the (-)-(3R) compound allows a clearer
structuire-activity-toxicity analysis and provides an improved therapeutic
ratio. It is therefore desirable to use the (-)-(3R) compound of the
present invention rather that the (3RS)-racemic mixture of Example 203.
Particular pharmaceutically-acceptable salts of the (-)-(3R) compound of
the invention include, for example, salts with acids affording
physiologically-acceptable anions, such as salts with mineral acids, for
example a hydrogen halide such as hydrogen chloride or hydrogen bromide,
suilphuric acid or phosphoric acid, and salts with organic acids, for
example trifluoroacetic acid. Other pharmaceutically-acceptable salts
include, for example salts with inorganic bases such as alkali metal and
alkaline earth metal salts e.g. sodium salts, ammonium salts, and salts
with organic amines and quaternary bases forming
physiologically-acceptable cations such as salts with methylamine,
dimethylamine, trimethylamine, ethylenediamine, piperidine, morpholine,
pyrriolidine, piperazine, ethanolamine, triethanolaminie,
N-methylglucamine, tectramethylammonium hydroxide and
benzyltrimethylammonium hydroxide.
Particular pharmaceutically-acceptable esters of the (-)-(3R) compound of
the invention include, for example, ester derivatives of the carboxylic
acid group in the compound of the invention, for example esters formed
with alcohols such as (1-6C)alcohols (e.g. methanol, ethanol, propanol and
tert-butanol), indanol, adamantol, (1-6C)alkanoyloxy-(1-4C)alcohols (e.g.
pivaloyloxymethanol) and (1-4C)alkoxycarbonyl-(1-4C)alcohols (e.g.
methoxycarbonylmethanol).
Particular pharmnaceutically-acceptable amides of the (-)-(3R) compound of
the invention include, for example, amide derivatives of the carboxylic
acid group in the compound of the invention, for example amides formed
with amines such as ammonia, (1-4C)alkylamines (e.g. methylamine),
di-(1-4C)alkylamines (e.g. dimethylamine, N-ethyl-N-methylamine and
diethylamine), (1-4C)alkoxy-(2-4C)alkylamines (e.g. 2-methoxyethylamine),
phenyl-(1-4C)alkylamines (e.g. benzylamine) and amino acids (e.g. glycine
or an ester thereof). Thus particular amides of the (-)-(3R) compound of
the invention include the N-methyl-,N,N-dimethyl-, N-ethyl-N-methyl- and
N,N-diethyl-butyramides.
Particular pharmaceutically-acceptable solvates of the (-)-(3R) compound of
the invention include, for example, hydrates e.g. a hemi-hydrate,
mono-hydrate, di-hydrate or tri-hydrate or an alternative quantity
thereof.
The phrase "substantially free of the (+)-(3S) stereoisomer" as used
hereinbefore means that there is at least 90% by weight of the (-)-(3R)
isomer and 10% by weight or less of the corriesponding (+)-(3S) isomer.
Preferably there is at least 95% by weight of the (-)-(3R) isomer and 5%
by weight or less of the (+)-(3S) isomer. More preferably there is at
least 99% by weight of the (-)-(3R) isomer and 1% by weight or less of the
(+)-(3S) isomer.
The (-)-(3R) compound of the invention, or a pharmacelutically-acceptable
salt, ester, amide solvate thereof may be prepared by any process known in
the art for the preparation of such a compound. Suitable procedures
include asymmetric synthesis involving an appropriate chiral intermediate
and resolution of the (3RS)-racemic mixture. Such procedures represent a
further feature of the invention and include the following:
a) Reaction of 4-4-(4-pyridyl)piperazin-1-yl!phenol, or a reactive
derivative thereof, with the chiral intermediate
(3R)-4-hydroxy-3-methylbutyric acid or an ester thereof, or a reactive
derivative thereof.
The reaction is conveniently performed in the presence of a strong base
such as an alkali metal hydride, for example, sodium hydride. Suitable
solvents include amides, such as dimethylformamide. The reaction is
conveniently performed at a temperature in the range of from 0.degree. to
100.degree. C.
Suitable esters of the chiral intermediate (3R)-4-hydroxy-3-methylbutyric
acid include, for example, the methyl, ethyl, propyl and tert-butyl
esters. Suitable reactive derivatives thereof include, for example,
(3R)-4-halogeno-3-methylbutyric acid or an ester thereof (e.g. a methyl or
ethyl ester) such as the 4-chloro and 4-bromo derivatives,
(3R)-4-alkanesulphonyloxy-3-methylbutyric acid or an ester thereof (e.g. a
methyl or ethyl ester) such as the 4-methanesulphonyloxy derivative or
(3R)-4-arylsulphonyloxy-3-methylbutyric acid or an ester thereof (e.g. a
methyl or ethyl ester) such as the 4-(p-toluenesulphonyloxy) derivative.
b) Reaction of a compound of formula I
##STR13##
in which L is a leaving atom or group, with the chiral intermediate
(3R)-3-methyl-4-4-(piperazin-1-yl)phenoxy!butyric acid, or an acid
addition salt thereof.
Examples of values for L include halogen, such as chlorine or bromine, and
cyanlo.
Examples of acid addition salts of
(3R)-3-methyl-4-4-(piperazin-1yl)-phenoxy!butyric acid include, for
example the hydrochlorides.
The reaction may conveniently be effected at a temperature in the range of
from -10.degree. to 120.degree. C., preferably from 10.degree. to
100.degree. C. Suitable solvents include, e.g. others such as
tetrahydrofuran and dioxan, amides such as dimethylformamide, nitriles
such as acetonitrile, halogenated hydrocarbons such as dichloromethane,
alcohols such as ethanol and water.
In some circumstances, for example when an acid addition salt of
(3R)-3-methyl-4-4-(piperazin-1-yl)phenoxy!butyric acid is used as
startling material, the reaction may advanitageously be performed in the
presence of a base. Examples of suitable bases include tertiary amines,
such as triethylamine, and alkali metal hydroxides, carbonates and
bicarbonates, such as sodium or potassium hydroxide, carbonate or
bicarbonate.
c) Decomposition of an ester of formula II
##STR14##
in which R is a carboxyl protecting group.
R may be any conventional carboxyl protecting group that may be removed
without interfering with other parts of the molecule. Examples of carboxyl
protecting groups include (1-6C)alkyl groups (such as methyl, ethyl,
propyl or t-butyl), phenyl and benzyl, the phenyl moiety in any of which
may optionally bear 1 or 2 of halogeno, (1-4C)alkyl, (1-4C)alkoxy or
nitro.
The decomposition may be carried out usinig any one of the conventional
reagents and conditions known in the art for converting carboxylic esters
into carboxylic acids. Thus, for example, the decomposition may be
performed by base catalysed hydrolysis, e.g. using an alkali metal
hydroxide such as lithium, potassium or sodium hydroxide, or a tertiary
amine such as triethylamine in the presence of water. The base catalysed
hydrolysis may be performed in the presence of a solvent such as an
alcohol, e.g. methanol or ethanol, or an ether such as tetrahydrofuLran or
dioxan. Alternatively the decomposition may be carried out by acid
catalysed hydrolysis, e.g. using aqueous acetic acid or trifluoroacetic
acid. The temperature is conveniently in the range of from -10.degree. to
100.degree. C., for example from 10.degree. to 50.degree. C. When the
alcohol residue is t-butyl, this may be removed by heating, e.g. at a
temperature in the range of from 80.degree. to 150.degree. C., alone or in
the presence of a suitable diluent such as diphenylether or
diphenylsulphone. A benzyl group may be removed by catalytic hydrogenation
, e.g. by hydrogenation in the presence of palladium on carbon at a
temperature in the range of from -10.degree. to 100.degree. C. in the
presence of a solvent such as an alcohol, for example methanol or ethanol.
d) Resolution of the (3RS)-racemic mixture,
(3RS)-3-methyl-4-{4-4-(4-pyridyl)piperazin-1-yl!phenoxy}butyric acid.
The resolution of the butyric acid derivative of the (3RS)-racemic mixture
may be carried out by conventional means, for example by salt formation
usinig an optically active base followed by separation, for example by
fractional crystallisation of the two salts so produced and regeneration
of the separated (-)-(3R) and (+)-(3S) compounds by acidification of the
separated salts.
The resolution of the butyric acid derivative of the (3RS)-racemic mixture
may also be carried out by the conventional means of forming a
diastereoisomeric pair of esters by reaction with an optically active
alcohol, separation of the esters, for example by chromatography, and
regeneration of the separate (-)-(3R) and (+)-(3S) compounds by hydrolysis
of the separated esters. An analogous route involving the preparation of a
diastereoisomeric pair of amides may also be employed.
Certain of the chiral intermediates defined hereinbefore are novel, thus
according to a further aspect of the invention there is provided the
compound tert-butyl (3R)-3-methyl-4-hydroxybutyrate, or a reactive
derivative thereof, substantially free of the (3S) stereoisomer. A
particular reactive derivative which may be mentioned is tert-butyl (3
R)-3-methyl-4-(p-toluenesulphonyloxy)butyrate.
The phrase "substantially free of the (3S) stereoisomer" as used
hereinbefore has the same meaning as given in relation to the (-)-(3R)
compound of the invention.
When a pharmaccutically-acceptable salt of the (-)-(3R) compound of the
invention is required, it may be obtained, for example, by reaction of
said compound with a suitable acid or base using a conventional procedure.
When a pharmaceutically-acceptable ester or amide of the (-)-(3R) compound
of the invention is required, it may be obtained, for example, by reaction
of said compound with a suitable alcohol or amine as appropriate using a
conventional procedure.
The ability of the (-)-(3R) compound of the invention to inhibit platelet
aggregation and to inhibit the binding of fibrinogen to GPIIb/IIIa may be
demonstrated using the standard test procedures (a) and (b) described
above.
The (-)-(3R) compound of the invention possesses activity against the
adenosine diphosphate (ADP) induced aggregation of human platelets with a
pA.sub.2 =7.3, and against the binding of fibrinogen to GPIIb/IIla with a
pIC.sub.50 =7.65.
As stated previously, the (-)-(3R) compound of the invention may be used in
the therapy or prevention of diseases in which cell adhesion (especially
platelet aggregation) is involved, for example venous or arterial
thrombosis (e.g. pulmonary embolism, stroke and thrombotic events
accompanying unstable angina and transient ischaemic attack), myocardial
infarction, atherosclerosis, thromboembolism and reocclusion during and
after thrombolytic therapy. The compounds may also be useful for the
prevention of reocclusion and restenosis following percutaneous
transluminal coronary angioplasty (PTCA) and coronary artery bypass graft.
It will also be appreciated that the compounds may be useful in the
treatment of other diseases mediated by binding of adhesion molecules to
GPIIb/IIIa, for example cancer.
According to a further aspect of the invention there is provided the use of
the (-)-(3R) compound, or a pharmaceutically-acceptable salt, ester, amide
or solvate thereof, substantially free of the (+)-(3S) stereoisomer as a
pharmaceutical.
According to a further aspect of the invention there is provided a method
of inhibiting platelet aggregation in a warm-blooded animal requiring such
treatment which comprises administering an effective amount of the
(-)-(3R) compound, or a pharmaccutically-acceptable salt, ester, amide or
solvate thereof, substantially free of the (+)-(3S) stereoisomer.
According to a further aspect of the invention there is provided a method
of inhibiting binding of fibrinogen to GPIIb/IIIa in a warm-blooded animal
requiring such treatment which comprises administering an effective amount
of the (-)-(3R) compound, or a pharmaceutically-acceptable salt, ester,
amide or solvate thereof, substantially free of the (+)-(3S) stereoisomer.
According to a further aspect of the invention there is provided a method
of inhibiting thrombotic events accompanying unstable angina in a
warm-blooded animal requiring such treatment which comprises administering
an effective amount of the (-)-(3R) compound, or a
pharmaceutically-acceptable salt, ester, amide or solvate thereof,
substantially free of the (+)-(3S) stereoisomer.
According to a further aspect of the invention there is provided a method
of inhibiting platelet aggregation in a warm-blooded animal requiring such
treatment while substantially reducing adverse effects associated with the
administration of the (3-RS)-racemic mixture, which comprises
administering an effective amount of the (-)-(3R) compound, or a
pharmaceutically-acceptable salt, ester, amide or solvate thereof,
substantially free of the (+)-(3S) stcreoisomer.
Pharmaceutical compositions of the (-)-(3R) compound may be formulated and
administered as described previously.
The invention will now be illustrated by the following non-limiting
Examples in which unless otherwise stated:
(i) concentrations and evaporations were carried out by rotary evaporation
in vacuo;
(ii) operations were carried out at ambient temperature, that is in the
range 18.degree.-26.degree. C;
(iii) column chromatography was carried out on silica (Merck Art. 9385)
available from E Merck and Co., Darmstadt, Germany; and on neutral alumina
(ICN Alumina N, Akt. I, III or IV) available from ICN Biomedicals GmbH,
D-3440 Eschwege, Germany;
(iv) yields are given for illustration only and are not necessarily the
maximum attainable by diligent process development;
(v) proton NMR spectra were normally determined at 200 MHz or 250 MHz in
dimethylsulphoxide-d.sub.6 using tetramethylsilane (TMS) as an internal
standard, and are expressed as chemical shifts (delta values) in parts per
million relative to TMS using conventional abbreviations for designation
of major peaks: s, singlet; m, multiplet; t, triplet; br, broad; d,
doublet; and
(vi) ether refers to diethyl ether, THF to tetrahydrofuran, DMF to
N,N-dimethylformamide, DMSO to dimethylsulphoxide, TFA to trifluoroacetic
acid; HOBT to 1-hydroxybenzotriazole; and NBA to m-nitrobenzylalcohol.
(vii) drying with PS paper refers to the use of Whatmans PS phase
separating paper.
EXAMPLE 1
Methyl 4-2-4-(4-pyridyl)piperazin-1-yl!acetyl!phenoxyacetate
A solution of methyl 4-bromoacetylphenoxyacetate (4.3 g) in acetonitrile
(50 ml) was added dropwise over 40 minutes to a stirred solution of1-
(4-pyridyl)piperazine (4.9 g) in acetonitrile (100 ml). Stirring was
continued for a further 1.5 hours, then the solution was filtered and the
filtrate evaporated in vacuo. The solid residue was triturated with water
(50 ml), then dried and suspended in methylene chloride (50 ml). The
suspension was then filtered and the filtrate concentrated to a small
volume. Purification by flash chromatography on neutral alumina eluting
first with dichloromethane, then 0.5% v/v methanol/dichloromethane and
finally 1% v/v methanol/dichloromethane gave the title compound, 1.93 g,
as a solid: m.p. 150.degree.-152.degree. C.; NMR (d.sub.6 DMSO) .gamma.
8.14(2H,d), 7.98(2H,d), 7.03(2H,d), 6.78(2H,d), 4.90(2H,s), 3.83(2H,s),
3.72(3H,s), 3.34(4H,bt), 2.65(4H,bt); m/e 370 (M+H).sup.+ ; calculated for
C.sub.20 H.sub.23 N.sub.3 O.sub.4 : C, 65.0; H, 6.3; N, 11.4. found: C,
65.2; H, 6.4; N, 11.3%.
EXAMPLE 2
4-2-4- (4-Pyridyl)piperazin-1-yl!phenoxyacetic acid
A stirred solution of the product of Example 1 (550 mg) in methanol (10 ml)
was treated with a M sodium hydroxide solution (1.65 ml) and stirring
continued for a further 2 hours. The mixture was diluted with water (10
ml) and the resulting solution concentrated in vacuo. Water (20 ml) was
added and then a M hydrochloric acid solution (1.65 ml). On cooling to
4.degree. C., a solid precipitated. This mixture was concentrated in
vacuo, the solid collected and washed with ice-water, then dried to give
the title compound, 320 mg, as a solid: m.p. 294.degree.-296.degree. C.;
NMR (d.sub.6 DMSO+TFA) .delta. 8.34(2H,d), 7.95(2H,d), 7.26(2H,d),
7.10(2H,d), 5.06(2H,s), 4.82(2H,s), 4.06(4H,bs), 3.52(4H,bs); m/e
356(M+H).sup.+ ; calculated for C.sub.19 H.sub.21 N.sub.3 O.sub.4 : C,
64.2; H, 6.0; N, 11.8. found: C, 64.1; H, 6.1; N, 11.6%.
EXAMPLE 3
Dimethyl
2,2'-4-2-4-pyridyl)piperazin-1-yl)!acetyl!phenylene-1,2-dioxy!diacetate
A solution of dimethyl 2,2'-(4-bromoacetyl)phenylene1,2-dioxy!diacetate
(3.0 g) in acetonitrile (15 ml) was added dropwise over 30 minutes to a
stirred solution of 1-(4-pyridyl)piperazine (2.6 g) in acetonitrile (75
ml) and the mixture stirred overnight. The mixture was then filtered and
the filtrate evaporated to give an oil. Purification by flash
chromatography on silica eluting first with 2.5% v/v
methanol/dichloromethane then 5% v/v methanol/dichloromethane gave a
solid. Trituration with ether gave the title compound, 0.95 g, as a solid:
m.p. 81.degree.-83.degree. C.; NMR (d.sub.6 DMSO) .delta. 8.14(2H,d),
7.67(1H,dd), 7.52(1H,d), 7.03(1H,d), 6.80(2H,d), 4.94(2H,s), 4.88(2H,s),
3.81(2H,s), 3.69(6H,s), 3.29(4H,t), 2.60(4H,t); m/c 458 (M+H).sup.+ ;
calculated for C.sub.23 H.sub.27 O.sub.7 N.sub.3. 0.25H.sub.2 O: C, 59.8;
H, 6.0; N, 9.1. found C, 59.7; H, 6.2; N, 8.8%.
The starting material was prepared as follows:
i) Methyl bromoacetate (19.1 ml) was added dropwise to a stirred mixture of
3,4-dihydroxyacetophenone (12.6 g) and anhydrous potassium carbonate (27.5
g) in acetone (250 ml). Stirring was continued for 16 hours when the
mixture was filtered and the solvent removed in vacuo. The residue after
trituration with ether gave dimethyl
2,2'-(4-acetyl)phenylene-1,2-dioxy)!diacetate, 13.1 g, as an off-white
solid: m.p. 101.degree.-102.degree. C.; NMR (d.sub.6 DMSO) .delta.
7.60(1H,dd), 7.41(1H,d), 7.02(1H,d), 4.94(2H,s), 4.89(2H,s), 3.71(6H,s),
2.50(3H,s); m/e 297(M+H).sup.+ ; calculated for C.sub.14 H.sub.16 O.sub.7
: C, 56.8; H, 5.4. found: C, 56.4; H, 5.5%.
ii) A solution of bromine (2.27 ml) in chloroform (10 ml) was added
dropwise over 15 minutes to a stirred solution of the product of step i)
(12.9 g) in chloroform (40 ml) at 30.degree. C.. The mixture was then
stirred for 2 hours at ambient temperature when the solvent was removed in
vacuo. The resulting waxy solid, on trituration with ethanol, gave
dimethyl 2,2'-(4-bromoacetyl!phenylene-1,2-dioxy)diacetate, 11.5 g, as a
cream solid: m.p. 76.degree.-78.degree. C.; NMR (d.sub.6 DMSO) .delta.
7.66(1H,dd), 7.47(1H,d), 7.06(1H,d), 4.96(2H,s), 4.90(2H,s), 4.62(2H,s),
3.71(6H,s); m/e 375/377 (M+H).sup.+, 1 Br pattern.
EXAMPLE 4
2,2'-4-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!phenylene-1,2-dioxy!diacetic
acid
A stirred solution of the product of Example 3 (300 mg) in methanol (4 ml)
was treated with a M sodium hydroxide solution (1.31 ml) and the mixture
stirred for 1 hour. The mixture was diluted with water (10 ) and the
resulting solution concentrated to about 7 ml when a M hydrochloric acid
solution (1.31 ml) was added. On cooling to 4.degree. C. the solid formed
was collected, then washed with ice-water and dried to give the title
compound, 120 mg, as a white solid: m.p. 180-184.degree. C. (dec); NMR
(d.sub.6 DMSO) .delta. 8.16(2H,d), 7.61(2H,t), 6.93(1H,d), 6.87(2H,d),
4.73(2H,s), 4.68(2H,s), 3.77(2H,s), 3.44(4H,bt), 2.58(4H,bt); m/e 430
(M+H).sup.+ ; calculated for C.sub.21 H.sub.23 O.sub.7 N.sub.3.
0.75H.sub.2 O: C, 56.9; H, 5.5; N, 9.5. found C, 57.0; H, 5.6; N, 9.3%.
EXAMPLE 5
Methyl 4-2-4-(4-pyridyl)piperazin-1-yl!acetyl!-2-methoxyphenoxyacetate
A solution of methyl 4-bromoacetyl 2-methoxyphenoxyacetate (1.27 g) in
acetonitrile (10 ml) was added dropwise over 15 minutes to a stirred
solution of 1-(4-pyridyl)piperazine (1.30 g) in acetonitrile (30 ml).
After stirring overnight the liquors were decanted from the solid residue,
then concentrated in vacuo. Purification by flash chromatography on
silica, eluting with dichloromethane then 5% v/v methanol/dichloromethane
gave a solid. Trituration with ether gave the title compound, 420 mg: m.p.
110-112.degree. C.; NMR (d.sub.6 DMSO) .delta. 8.14(2H,d), 7.65(1H,dd),
7.55(1H,d), 6.97(1H,d), 6.80(2H,d), 4.90(2H,s), 3.87(5H,s), 3.72(3H,s),
3.33(4H,t), 2.62(4H,t); m/e 400(M+H).sup.+ ; calculated for C.sub.21
H.sub.25 N.sub.3 O.sub.5 : C, 63.1; H, 6.3; N, 10.5. found: C, 62.9; H,
6.3; N, 10.4%.
EXAMPLE 6
4-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!-2-methoxyphenoxyacetic acid
In a similar manner to Example 2, but starting from the product of Example
5, the title compound was prepared in 47% yield: m.p.
218.degree.-224.degree. C.; NMR (d.sub.6 DMSO) .delta. 8.16(2H,d),
7.65(1H,dd), 7.53(1H,d), 6.92(1H,d), 6.85(2H,d), 4.73(2H,s), 3.86(2H,s),
3.82(3H,s), 3.36(4H,t), 2.63(4H,t); m/e 386(M+H).sup.+ ; calculated for
C.sub.20 H.sub.23 N.sub.3 O.sub.5. H.sub.2 O: C, 59.5; H, 6.2; N, 10.4.
found: C, 59.5; H, 5.9; N, 10.1%.
EXAMPLE 7
Methyl 4-3-4-(4-pyridyl)piperazin-1-yl!propanoyl!phenoxyacetate
In a similar manner to Example 3, but starting from methyl
4-3-chloropropanoyl!phenoxyacetate was prepared the title compound in 65%
yield: m.p. 93.degree.-95.degree. C.; NMR(d.sub.6 DMSO) .delta.
8.14(2H,d), 7.96(2H,d), 7.04(2H,d), 6.81(2H, d), 4.92(2H, s), 3.71(3H,s),
3.29(4H,t), 3.17(2H,t), 2.72(2H,t), 2.51(4H,t); m/c 384 (M+H).sup.+ ;
calculated for C.sub.21 H.sub.25 N.sub.3 O.sub.4 C, 65.8; H, 6.6; N, 11.0.
found C, 65.6; H, 6.8; N, 10.8%.
The starting material was prepared as follows:
i) Aluminium chloride (33.35 g) was added portionwise to a stirred cooled
(<0.degree. C.) solution of methyl phenoxyacetate (14.46 ml) and
3-chloroproponyl chloride (9.55 ml) in dichloromethane (500 ml). After the
addition the ice-bath was removed and the mixture stirred for 1 hour when
it was poured into ice-water (500 ml). The organic phase was separated and
the aqueous portion extracted two times with dichloromethane. The combined
dichloromethane extracts were washed with water, then brine and dried
(MgSO.sub.4). The residue, after removal of the solvent in vacuo and
trituration with ether gave methyl 4-3-chloropropanoyl!phenoxyacetate,
22.3 g, as a solid: m.p. 89.degree.-90.degree. C.; NMR (d.sub.6 DMSO)
.delta. 7.95(2H,d), 7.05(2H,d), 4.92(2H,s), 3.91(2H,t), 3.71(3H,s),
3.49(2H,t); m/e 257(M+H).sup.+ ; calculated for C.sub.12 H.sub.13
ClO.sub.4 : C, 56.1; H, 5.0. found: C, 55.8; H, 5.1%.
EXAMPLE 8
4-3-4-(4-Pyridyl)piperazin-1-yl!propanoyl!phenoxyacetic acid
In a similar manner to Example 2, but starting from the product of Example
7, the title compound was prepared in 60% yield: m.p.
238.degree.-239.degree. C.; NMR (d.sub.6 DMSO+d.sup.4 acetic acid) .delta.
8.21(2H,d), 7.97(2H,d), 7.15(2H,d), 7.02(2H,d), 4.77(2H,s), 3.64(4H,t),
3.21(2H,t), 2.82(2H,t), 2.62(4H,t); m/e 370(M+H).sup.+ ; calculated for
C.sub.20 H.sub.23 N.sub.3 O.sub.4 : C, 65.0; H, 6.3; N, 11.4. found C,
64.6; H, 6.4; N, 11.1%.
EXAMPLE 9
Methyl 4-2-4-(4-pyridyl)piperazin-1-yl!acetyl!phenylthioacetate
In a similar manner to Example 3, but starting fiom methyl
4-bromoacetylphenylthioacctate, the title compound was prepared in 27%
yield: m.p. 109.degree.-110.degree. C.; NMR (d.sub.6 DMSO) .delta.
8.15(2H,d), 7.93(2H, d), 7.40(2H,d), 6.80(2H,d), 4.07(2H,s), 3.86(2H,s),
3.66(3H,s), 3.30(4H,t), 2.61(4H,t); m/e 386 (M+H).sup.+ ; calculated for
C.sub.20 H.sub.23 N.sub.3 O.sub.3 S. 0.25 H.sub.2 O: C, 61.4; H, 6.0; H,
10.7. found C, 61.8; H, 6.0; H, 10.6%.
The starting material was prepared as follows:
i) Aluminium chloride (18.03 g) was added portionwise to a stirred cooled
(<5.degree. C.) solution of methyl phenylthioacetate (9.84 g) and
bromoacetyl chloride (4.46 ml) in dichloromethane (250 ml) keeping the
temperature below 5.degree. C. The mixture was then stirred for one hour
at ambient temperature then poured onto ice. After a filtration, the
organic phase was separated and the aqueous portion extracted two times
with dichloromethane. The combined dichloromethane extracts were washed
with brine, dried (MgSO.sub.4), filtered and evaporated to give
4-bromoacetylphenylthioacetate; 11.52 g, as a solid: m.p.
48.degree.-50.degree. C.; NMR (CDCl.sub.3) .delta. 7.91(2H,d), 7.40(2H,d),
4.39(2H,s), 3.76(5H,s); m/e 302/304 (M+H).sup.+, 1 Br pattern.
EXAMPLE 10
4-2-4-(4-Pyridyl)piperazin-1-yl!acetate!phenylthioacetic acid
In a similar manner to Example 2, but starting from the product of Example
9, the title compound was prepared in 83% yield: m.p.
240.degree.-244.degree. C.; NMR (d.sub.6 DMSO) .delta. 8.16(2H,d),
7.93(2H,d), 7.39(2H,d), 6.66(2H,d), 3.92(2H,s), 3.86(2H,s), 3.38(4H,t),
2.64(4H,t); m/e 372(M+H).sup.+ ; calculated for C.sub.19 H.sub.21 N.sub.3
O.sub.3 S. 0.25H.sub.2 O: C, 60.6; H, 5.7; N, 11.2. found C, 60.5; H, 5.6;
N, 10.8%.
EXAMPLE 11
Methyl 3-4-2-4-(4-pyridyl)piperazin-1-yl!acetyl!phenyl!propionate
A solution of methyl 3-(4-bromoacetylphenyl)propionate (380 mg) in
acetonitrile (4 ml) was added dropwise over 15 minutes to a stirred
solution of 1-(4-pyridyl)piperazine (450 mg) in acetonitrile (10 ml) and
the mixture stirred overnight. The mixture was then filtered and the
filtrate concentrated in vacuo to give an oil. Purification by flash
chromatography on silica eluting first with dichloromethane then 5% v/v
methanol/dichloromethane gave a solid. Trituration with ether gave the
title compound, 172 mg, as a solid: m.p. 141.degree.-143.degree. C.; NMR
(d.sub.6 DMSO) .delta. 8.15(2H,d), 7.92(2H,d), 7.37(2H,d), 6.83(2H,d),
3.89(2H,s), 3.59(3H,s), 3.37(4H,t), 2.93(2H,t), 2.69(2H,t), 2.65(4H,t);
m/e 368(M+H).sup.+ ; calculated for C.sub.21 H.sub.25 N.sub.3
O.sub.3.0.25H.sub.2 O: C, 67.8; H, 6.9; N, 11.3. found: C, 67.8; H, 6.9;
N, 11.1%.
EXAMPLE 12
3-4-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!phenyl!propionic acid
A stirred solution of the product of Example 11 (70 mg) in methanol (0.5
ml) was treated with a M sodium hydroxide solution (0.19 ml) and stirring
continued for 3 hours. The methanol was removed in vacuo and the residue
diluted with water (1 ml), then a M hydrochloric acid solution (0.19 ml)
added. On cooling to 4.degree. C. a solid precipitated which was
collected, washed with ice-water, then dried to give the title compound,
36.5 mg: m.p. 245.degree.-247.degree. C.; NMR (d.sub.6 DMSO) .delta.
8.05(2H,d), 7.91(2H,d), 7.36(2H,d), 6.86(2Hd), 3.89(2H,s), 3.34(4H,t),
2.87(2H,t), 2.62(4H,t), 2.58(2H,t); m/e 354 (M+H).sup.+ : calculated for
C.sub.20 H.sub.23 N.sub.3 O.sub.3.0.2H.sub.2 O: C, 67.2; H, 6.6; N, 11.8.
found: C, 67.6; H, 6.6; N, 11.4%.
EXAMPLE 13
Methyl 4-2-4-(4-pyridyl)piperazin-1-yl!acetyl!phenylacetate
A solution of methyl 4-chloroacetylphenylacetate (260 mg) in acetonitrile
(4 ml) was added dropwise over 15 minutes to a stirred solution of
1-(4-pyridyl)piperazine (375 mg) in acetonitrile (10 ml) and the mixture
stirred overnight. The supernatent was decanted from the solid formed,
concentrated in vacuo and purified by flash chromatography on neutral
alumina, eluting with dichloromethane then 0.25% v/v
methanol/dichloromethane and finally 0.5% v/v methanol dichloromethane.
Concentration of the fractions in vacuo gave the title compound, 96 mg, as
a white crystalline solid: m.p. 127.degree.-129.degree. C.; NMR (d.sub.6
DMSO) .delta. 8.15(2H,d), 7.98(2H,d), 7.41(2H,d), 6.81(2H,d), 3.91(2H,s),
3.78(2H,s), 3.53(3H,s), 3.33(4H,t), 2.64(4H,t); m/e 354(M+H).sup.+ ;
calculated for C.sub.20 H.sub.23 N.sub.3 O.sub.3 : C, 68.0; H, 6.6; N,
11.9. found: C, 68.2; H, 6.6; N, 11.9%.
EXAMPLE 14
Ethyl 4-2-4-(4-pyridyl)piperazin-1-yl!acetyl!phenylacetate
Using a method similar to that of Example 13, but starting from ethyl
4-chloroacetylphenylacetate and purification by flash chromatography on
silica, eluting with dichloromethane then 5% v/v methanol/dichloromethane,
the title compound was prepared in 13% yield as solid: m.p.
122.degree.-124.degree. C.; NMR (d.sub.6 DMSO) .delta. 8.01(2H,d),
7.29(2H,d), 7.25(2H,d), 6.67(2H,d), 3.93(2H,q), 3.75(2H,s), 3.60(2H,s),
3.18(4H,t), 2.47(4H,t), 1.03(3H,t); m/e 368 (M+H).sup.+ ; calculated for
C.sub.21 H.sub.25 N.sub.3 O.sub.3 : C, 68.6; H, 6.9: N, 11.4. found: C,
68.2; H, 6.8; N, 11.3%.
EXAMPLE 15
4-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!phenylacetic acid,
trifluoroacetate salt
A stirred solution of the product of Example 13 (142 mg) in methanol (1 ml)
was treated with M sodium hydroxide solution (0.46 ml) and stirring
continued for 2 hours. The methanol was removed invacuo, the residue
diluted with water (1 ml), then a Mhydrochloric acid solution (0.46 ml)
was added. This solution was transferred to a 1 inch preparative reverse
phase hplc column (VYDAC.sup.R 218TP1022) and eluted with water,
acetonitrile/trifluoroacetic acid in a gradient from 98:2:0.1 v/v/v to
75:25:0.1 v/v/v. The pure fractions, on freeze-drying gave, the title
compound 96 mg, as a foam: NMR (d.sub.6 DMSO) .delta. 8.34(2H,d),
7.95(2H,d), 7.48(2H,d), 7.25(2H,d), 4.67(2H,b), 3.93(4H,b), 3.72(2H,s),
3.20(4H,b); m/e 340 (M+H).sup.+ ; calculated for C.sub.19 H.sub.21 N.sub.3
O.sub.3. 2.25 CF.sub.3 COOH: C, 47.4; H, 3.9; N, 7.1. found: C, 47.8; H,
3.8; N, 7.0%.
EXAMPLE 16
(RS) Methyl
4-2-4-(4-pyridyl)piperazin-1-yl!-2-methylacetyl!phenoxyacetate
A solution of RS methyl 4-(2-methylbromoacetyl)phenoxyacetate (1.2 g) in
acetonitrile (10 ml) was added dropwise over 30 minutes to a stirred
solution of 1-(4-pyridyl)piperazine (1.3 g) in acetonitrile (30 ml) and
the mixture stirred overnight. The mixture was then filtered and the
filtrate evaporated to give an oil. Purification by flash chromatography,
eluting first with dichloromethane then successively 2.5%, 3%, 4%, 5% and
10% v/v methanol/dichloromethane gave the title compound, 220 mg as a
solid: m.p. 81.degree.-83.degree. C.; NMR (d.sub.6 DMSO) .delta.
8.13(2H,d), 8.06(2H,d), 7.02(2H,d), 6.77(2H,d), 4.92(2H,s), 4.33(1H,q),
3.72(3H,s), 3.26(4H,t), 2.63(4H,t), 1.16(3H,d); m/e 384(M+H).sup.+ ;
calculated for C.sub.21 H.sub.25 N.sub.3 O.sub.4 : C, 65.8; H, 6.6; N,
11.0. found C, 65.7; H, 6.8; N, 10.9%.
EXAMPLE 17
RS 4-2-4-(4-Pyridyl)piperazin-1-yl!2-methylacetyl!phenoxyacetic acid
sodium chloride adduct dihydrate
A stirred solution of the product of Example 16, (110 mg) in methanol (1
ml) was treated with a M sodium hydroxide solution (0.32 ml) and stirTing
continued overnight. The methanol was removed in vacuo and the residue
diluted with water and a M hydrochloric acid solution (0.32 ml) added. The
solvent was removed in vacuo to give a yellow foam which, on trituration
with ether gave the title compound, 116 mg: NMR (d.sub.6 DMSO) .delta.
8.17 (2H,d), 8.06(2H,d), 7.01(2H,d), 6.98(2H,d), 4.76(2H,s), 4.37(1H,q).
3.47(4H,t), 1.16(3H,d), m/e 370 (M+H).sup.+ ; calculated for C.sub.20
H.sub.23 N.sub.3 O.sub.4.NaCl.2H.sub.2 O: C, 51.8; H,5.8;N, 9.1. found:
C,52.0; H, 5.6; N, 8.9%.
EXAMPLE 18
2,2'-4-3-4-(4-Pyridyl)piperazin-1-yl!propanoyl!phenylene-1,2-dioxy!diace
tate, trifluoroacetate salt
Di-tertiary butyl 2,2'-4-3-4-(4-pyridyl)piperazin-1
-yl!propanoyllphenylene-1,2-dioxy!diacetate (555 mg) was dissolved in 90%
v/v trifluoroacetate acidjwater (15 ml) and the mixture stirred for one
hour. The solvent was removed by evaporation in vacuo and the residual oil
on trituration with ether gave the title compound, 608 mg, as a solid:
m.p. 42.degree.-44.degree. C.; NMR (d.sub.6 DMSO) .delta. 8.26(2H,d),
7.15(2H,d), 6.80(3H,m), 4.67(2H,s), 4.63(2H,s), 3.65(8H,b), 3.39(1H,q),
2.75(2H,m), 2.66(2H,m), 1.09(1.5H,t); m/e 444 (M+H).sup.+ ; calculated for
C.sub.22 H.sub.25 N.sub.3 O.sub.7. 1.3 CF.sub.3 COOH. 1H.sub.2 O. 0.25
C.sub.4 H.sub.10 O: C, 48.9; H, 4.9; N, 6.7. found C, 49.1; H, 5.0; N,
6.3%; calculated CF.sub.3 COOH; 23.6. found 23.2%.
The starting material was prepared as follows:
i) Solid sodium hydride (1.6 g of a 60% w/w dispersion in mineral oil) was
added to a stirred, cooled (4.degree. C.) solution of
3,4-dihydroxybenizaldehyde (2.76 g) in THF (50 ml). The mixture was then
stirred for a further 15 minutes at ambient temperature, cooled to
4.degree. C. when tertiary butyl bromoacetate (6.5 ml) was added followed
by DMF (5 ml). After one hour the mixture was diluted with ether (100 ml),
washed with water and brine, then dried (MgSO.sub.4) and evaporated to
give a solid. Recrystallisation from cyclohexane gave di-tertiary butyl
2,2'-(4-formyl!)phenylene-1,2-dioxy)diacetate, 4.1 g, as pale yellow
crystals: m.p. 96.degree. C.; NMR (d.sub.6 DMSO) .delta. 9.82(1H,s),
7.54(1H,dd), 7.33(l H,d), 7.08(1H,d), 4.82(2H,s), 4.75(2H,s), 1.43(18H,s),
rnle 366 (M+); calculated for C.sub.19 H.sub.26 O.sub.7 ; C, 62.4; H, 7.3.
found C, 62.3; H, 7.2%.
ii) To a solution of the product of step i) (10.0 g) and malonic acid (42
g) in pyridine (150 ml) was added a few drops of piperidine and the
mixture heated on a steam-bath for 4 hours. The pyridine was removed in
vacuo, water 300 ml added and the mixture extracted with ether
(3.times.100 ml). The combined extracts were washed with water, brine,
dried (MgSO.sub.4) then evaporated to give a gum. Recrystallisation from
cyclohexane gave di-tertiary butyl 2,2'-(4-(3-propenoic
acid)!phenylene-1,2-dioxy)diacetate. 0.5 cyclohexane adduct, 6.6 g, m.p.
104.degree.-106.degree. C.; NMR (d.sub.6 DMSO) .delta. 12.20(1 H,b),
7.48(l H,d), 7.26(1 H,s), 7.20(1H,d), 6.89(1H,d), 6.40(1H,d), 4.74(2H,s),
4.72(2H,s), 1.43(188H,s), 1.40(6H,s); m/e 408 (M+).
iii) 10% w/w palladium on charcoal (250 mg) was added to a solution of the
product of step ii) (2.05 g) in ethyl acetate (100 ml) and the mixture
hydrogenated at room temperature and pressure until the theoretical amount
of hydrogen had been taken up. Charcoal was added, the mixture stirred for
5 minutes then filtered through diatomaneous earth and the filtrate
evaporated to dryness giving di-tertiary butyl
2,2'-(4-1-(2-carboxyethyl)lphenylene-1,2-dioxy)diacetate, 1.9 g, as a
colourless gum: NMR (CDCl.sub.3) .delta. 6.76(3H,m), 4.58(2H,s),
4.56(2H,s), 2.86(2H,t), 2.60(2H,t), 1.47(18H,s); m/e 410(M+). This gum
slowly crystallised to give a white solid of m.p. 68.degree.-70.degree.
C.; calculated for C.sub.21 H.sub.30 O.sub.8 : C, 61.5; H, 7.4. found:
C,61.7; H, 7.7%.
iv) To a stirred solution of the product of step iii) (615 mg) in dry DMF
was added N,N'-diiosopropylethylamine (0.78 ml), HOBT (230 mg),
2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
(596 mg). After 15 minutes 1-(4-pyridyl)piperazine (245 mg) was added and
stirring continued overnight. The DMF was removed in vacuo, the resulting
oil partitioned between ethyl acetate (60 ml), and water (20 ml). The
organic phase was separated, washed successively with water (20 ml), M
sodium hydroxide solution (20 ml), brine (3.times.20 ml) then dried and
the solvent evaporated to give an oil. Purification of this oil by flash
chromatography on silica, eluting with 6.5% v/v methanol in
dichloromethane gave di-tertiary butyl
2,2'-4-3-4-(4-pyridyl)piperazin-1-ylpropanoyl!phenylene-1,2-dioxy!diace
tate, 728 mg, as a froth: m.p. 57.degree.-61.degree. C., NMR (d.sub.6 DMSO)
.delta. 8.16(2H,d), 6.80(5H,m), 4.63(2H,s), 4.59(2H,s), 3.58(4H,b),
3.32(4H,b), 2.73(2H,m), 2.61(2H,m), 1.45(18H,s); m/e 556(M+H).sup.+ ;
calculated for C.sub.30 H.sub.41 N.sub.3 O.sub.7. 0.5H.sub.2 O: C, 63.8;
H, 7.5; N, 7.4. found: C, 63.5; H, 7.4; N, 7.1%.
EXAMPLE 19
N-4-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!phenyl-4-methylphenyl!-sulphona
mide
A mixture of 1-(4-pyridyl)piperazine (1.79 g),
N-(4-bromoacetylphenyl)-4-methylphenylsulphonamide (3.68 g) and
triethylamine (1.39 ml) in isopropanol (50 ml) was stirred for 18 hours.
The precipitated solid was collected, triturated with dichloromethane,
filtered and dried. This solid was further purified by flash
chromatography on neutral alumina eluting successively with
dichloromethane, 2.5% v/v methanol/dichloromethane then 5% v/v
methanol/dichloromethane. Evaporation of the desired fractions to a small
volume followed by addition of dichloromethane gave a crystalline solid.
This solid was collected, washed with dichloromethane to give the title
compound, 440 mg, as crystals: m.p. 168.degree.-170.degree. C.; NMR
(d.sub.6 DMSO) .delta. 8.14(2H,d), 7.86(2H,d), 7.71(2H,d), 7.35(2H,d),
7.18(2H,d), 6.80(2H,d), 3.79(2H,s), 3.31(4H,t), 2.59(4H,t), 2.33(3H,s);
m/e 451 (M+H).sup.+ ; calculated for C.sub.24 H.sub.26 N.sub.4 O.sub.3 S:
C, 64.0; H, 5.8; N, 12.4. found C, 63.4; H, 5.7; N, 12.2%.
EXAMPLE 20
N-4-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!phenyl-1-butanesulphonamide
A solution of N-(4-bromoacetylphenyl)-1-butanesulphonamide (410 mg) in
acetonitnile (10 ml) was added to a stirred solution of
1-(4-pyridyl)piperazine (400 mg) in acetonitrile (10 ml) and the mixture
stirred for 18 hours. The solvent was removed in vacuo and the residue
purified by flash chromatography on silica eluting with 20% v/v
methanol/dichloromethane then on neutral alumina eluting with 2% v/v
methanol/dichloromethane. The residue, after evaporation of the eluant
fraction was triturated with ether to give
N-(4-(4-pyridylpiperazin-1-yl)acetyl!phenyl)-1-butanesulphonamide, 166
mg, as a white solid: m.p. 185.degree.-189.degree. C. dec; NMR (d.sub.6
DMSO) .delta. 8.13(2H,d), 7.98(2H,d), 7.28(2H,d), 6.79(2H,d), 3.82(2H,d),
3.32(4H,t), 3.15(2H,m), 2.63(4H,t), 1.65(2H,m), 1.36(2H,m), 0.83(3H,t);
m/e 417 (M+H).sup.+ ; calculated for C.sub.21 H.sub.28 N.sub.4 O.sub.3 S:
C, 60.6; H, 6.8; N, 13.5. found C,60.5; H, 6.8; N, 13.1%.
EXAMPLE 21
N-4-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!phenyl!methyl-4-methylphenylsul
phonamide
A solution of N-(4-bromoacetylphenyl!methyl)-4-methylphenylsulphonamide
(470 mg) in acetonitrile (10 ml) was added to a stirred solution of
1-(4-pyridyl)piperazine (400 mg) in acetonitrile (10 ml) and the mixture
stirred for 18 hours. The solvent was evaporated in vacuo and the residue
purified by flash chromatography on silica, eluting with 10% v/v
methanol/dichloromethane. On evaporation of the eluant fraction to a small
volume crystallisation occurred. These crystals, on filtration and washing
with dichloromethane gave the title compound, 130 mg, as a solid: m.p.
215.degree.-219.degree. C. dec; NMR (d.sub.6 DMSO) .delta. 8.14(3H,m),
7.91(2H,d), 7.69(2H,d), 7.38(4H,d), 6.82(2H,d), 4.03(2H,d), 3.89(2H,s),
3.32(4H,t), 2.62(4H,t), 2.39(3H,s); m/e 465(M+H).sup.+ ; calculated for
C.sub.25 H.sub.28 N.sub.4 O.sub.3 S: C, 64.6; N, 6.1; N, 12.1. found C,
64.7; H, 6.2; N, 12.0%.
The starting material was prepared as follows:
i) To a stirred suspension under argon of 4-acetylbenzylamine hydrochloride
(700 mg) in dichloromethane (20 ml) was added triethylamine (1.15 ml) and
stirring continued for 15 minutes. The mixture was cooled to 4.degree. C.,
then 4-methylphenylsulphonyl chloride (790 mg) in dichloromethanie (5 ml)
added dropwise over 30 minutes. The reaction mixture was stirred for 18
hours at ambient temperature, then diluted with further dichloromethane
(50 ml), washed with water, dried (MgSO.sub.4) and evaporated. Trituration
of the residue gave N-(4-acetylphenyl!methyl)-4-methylphenysulphonamide
(A), 1.02 g., as an off-white solid: m.p. 125.degree.-128.degree. C.; NMR
(d.sub.6 DMSO) .delta. 8.13(1H,t), 7.86(2H,d), 7.68(2H,d), 7.37(4H,dd),
4.03(2H,d), 2.55(3H,s), 2.39(3H,s); m/e 304(M+H).sup.+.
ii) A mixture of the product of step i) (1.0 g) and cupric bromide (1.47 g)
in ethyl acetate (3.0 ml) was heated at reflux temperature for 16 hours.
Additional cupric bromide (1.0 g) was added and heating continued for a
further 8 hours. The mixture was filtered and the filtrate concentrated to
dryness in vacuo. This residue was purified by flash chromatography on
silica, eluting with hexane/ethyl acetate (2:1 v/v). Evaporation of the
fractions gave N-(14-bromoacetylphenyl!methyl)-4-methylphenylsulphonamide,
1.13 g, as a white solid: m.p. 116.degree.-117.degree. C., NMR (CDl.sub.3)
.delta. 7.9(2H,d), 7.75(2H,d), 7.34(4H,m), 4.77(1H,t), 4.40(2H,s),
4.22(2H,d), 2.44(3H,s): m/e 382/384 (M+H).sup.+, 1 Br pattern.
EXAMPLE 22
N-4-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!phenyl!methyl-1-butanesulphonam
ide
In a similar manner to Example 21 but starting from
N-4-bromoacetylphenyl!methyl- 1-butanesulphonamide the title compound was
obtained as a solid in 25% yield: m.p. 158.degree.-160.degree. C.; NMR
(d.sub.6 DMSO) .delta. 8.14(2H,d), 7.98(2H,d), 7.68(lH,t), 7.48(2H,d),
6.83(2H, d) 4.22(2H,d), 3.90(2H,s), 3.32(4H,t), 2.94(2H,m), 2.63(4H,t),
1.60(2H,m), 1.32(2H,m), 0.84(3H,t); m/e 431 (M+H).sup.+ ; calculated for
C.sub.22 H.sub.30 N.sub.4 O.sub.3 S. 0.5 H.sub.2 O: C, 60. 1; H, 7.1; N,
12.8. found: C,60.5; H, 7.2; N. 12.8%.
The starting material was prepared as follows:
i) In a similar manner to Example 21i) but starting from 1-butanesulphonyl
chloride there was obtained, after flash chromatography on silica eluting
with ethyl acetate/hexane (1:1 v/v),
N-(4-acetylphenyl!methyl)l-butanesulphonamide in 89% yield as a white
crystalline solid: m.p. 87.degree.-89.degree. C.; NMR (d.sub.6 DMSO)
.delta. 7.93(2H,d), 7.67(1H,t), 7.49(2H,d), 4.22(2H,d), 2.95(2H,m),
2.56(3H,s), 1.61(2H,m), 1.32(2H,m), 0.86(3H,s); m/e 270 (M+H).sup.+.
ii) In a similar manner to Example 21ii) but starting from the product of
step i) above, there was obtained, after chromatography on silica eluting
with hexane/ethyl acetate (2:1 Iv/v),
N-(4-bromoacetylphenyl!methyl)-1-butanesulphonamide as off-white crystals
in 70% yield: m.p. 101.degree.-103.degree. C.; NMR (d.sub.6 DMSO) .delta.
7.99(2H,d), 7.69(1H,t), 7.52(2H,d), 4.49(4.23(2H,d), 2.96(2H,m),
1.60(2H,m), 1.33(2H,m), 0.86(3H,s); m/e 365/367 (M+NH.sub.4).sup.+, 1 Br
pattern.
EXAMPLE 23
N-2-4-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!phenyl!ethyl!-4-methylphenyl
sulphonamide
A solution of N-(2-4-bromoacetylphenyl!ethyl)-4-methylphenylsulphonamide
(485 mg) in acetonitrile (10 ml) was added to a stirred solution of
l-(4-pyridyl)piperazine (400 mg) in acetonitrile (10 ml) and the mixture
was stirred for 18 hours. The solvent was evaporated in vacuo and the
residue purified by flash chromatography on silica, eluting with 10% v/v
methanol/dichloromethane. On evaporation of the eluant fraction
crystallisation occured. These crystals on filtration and washing with
dichloromethane gave the title compound, 230 mg, as an off-white solid:
m.p. 133.degree.-135.degree. C.; NMR (d.sub.6 DMSO) .delta. 8.14(2H,bd),
7.90(2H,d), 7.65(2H,d), 7.59(1H,t), 7.35(2H,d), 7.29(2H,d), 6.81(2H,d),
3.37(2H,s), 3.33(4H,t), 2.98(2H,q), 2.76(2H,t), 2.63(4H,t), 2.38(3H,s);
m/e 479(M+H).sup.+ ; calculated for C.sub.26 H.sub.30 N.sub.4 O.sub.3 S:
C, 65.2; H, 6.3; N, 11.7; found. C 65.0; H, 6.3; N, 11.4%.
The starting material was prepared as follows:
i) To a stirred suspension under argon of 4-acetylphenethylamine
hydrochloride (1 g) in dichloromethane (20 ml) was added triethylamine
(0.94 ml) and stirring continued for 15 minutes. The mixture was cooled to
4.degree. C., then 4-methylphenylsulphonyl chloride (1.29 g) in
dichloromethane (5 ml) added dropwise over 30 minutes. The reaction
mixture was stirred for 18 hours at ambient temperatuLe, then diluted with
further dichloromethanie (50 ml), washed with water, dried (MgSO.sub.4)
and evaporated. Trituration of the residue gave
N-(2-4-acetylphenyl!ethyl)-4-methylphenylsulphonamide, 1.58 g, as a
yellow crystalline solid: m.p. 124.degree.-126.degree. C.; NMR (d.sub.6
DMSO) .delta. 7.84(2H,d), 7.63(3H,m), 7.37(2H,d), 7.29(2H,d), 2.98(2H,q),
2.75(2H,t), 2.55(3H,s), 2.39(3H,s); m/e 318(M+H).sup.+.
ii) A mixture of the product of step i) (1.5 g) and cupric bromide (2.1 g)
in ethyl acetate (50 ml) was heated at reflux temperature for 16 hours.
The mixture was filtered, and the filtrate concentrated to dryness in
vacuo. This residue was purified by flash chromatography on silica,
eluting with hexane/ethyl acetate (2:1 v/v). Evaporation of the fractions
gave N-(2-4-bromoacetylphenyl!ethyl)-4-methylphenylsulphonamide, 860 mg,
as a white crystalline solid: m.p. 133.degree.-136.degree. C.; NMR
(CDCl.sub.3) .delta. 7.90(2H,d), 7.70(2H,d), 7.29(2H,d), 7.22(2H,d),
4.41(2H,s), 4.29(1H,t), 3.26(2H,q), 2.86(2H,t), 2.43(3H,s), m/e
396/398(M+H).sup.+, 1 Br pattern.
EXAMPLE 24
N-2-4-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!phenyl!ethyl!-1-butanesulpho
namide
In a similar manner to Example 23 but starting from
N-(2-4-bromoacetylphenyl!-ethyl)-1-butanesulphonamide the title compound
was obtained, after trituration of the residual gum from flash
chromatography with ether, in 22% yield: m.p. 74-80.degree. C. (dec); NMR
(d.sub.6 DMSO) .delta. 8.15(2H,d), 7.94(2H,d), 7.39(2H,d), 7.1O(1H,t),
6.64(2H,d), 3.70(2H,s), 3.37(4H,t), 3.21(2H,q), 2.85(4H,m), 2.64(4H,t),
1.52(2H,m), 1.31(2H,m), 0.84(3H,t); m/e 445 (M+H).sup.+ ; calculated for
C.sub.23 H.sub.32 N.sub.4 O.sub.3 S. 0.5 H.sub.2 O: C, 60.9; H, 7.3; N,
12.4. found: C, 60.5; H, 7.3; N, 12.1%.
The starting material was prepared as follows:
i) In a similar manner to Example 23i) but starting from 1-butanesulphonyl
chloride there was obtained, after purification by flash chromatography on
silica eluting with ethyl acetate hexane (1:1 v/v),
N-(2-4-acetylphenyl!ethyl) 1-butanesulphonamide in 65% yield as a white
crystalline solid: m.p. 75.degree.-76.degree. C.; NMR (d.sub.6 DMSO)
.delta. 7.90(2H,d), 7.40(2H,d), 7.09(1H,t), 3.20(2H,q), 2.88(4H1,m),
2.57(3H,s), 1.53(2H,m), 1.31(2H,m), 0.84(3H,s); m/e 284 (M+H).sup.+.
ii) In a similar manner to Example 23ii) but starting from the product of
step i) above, there was obtained, after chromatography on silica eluting
with hexane/ethyl acetate (2:1 v/v), N-(2-4-bromoacetylphenyllethyl)
1-butanesulphonamide in 54% yield as pale yellow crystals: m.p.
84.degree.-86.degree. C.; NMR (CDCl.sub.3) .delta. 7.96(2H,d), 7.36(2H,d),
4.42(2H,s), 4.12(1H,t). 3.43(2H,q), 2.96(4H,m), 1.72(2H,m), 1.41 (2H,m),
0.92(3H,t); m/e 379/381 (M+NH.sub.4).sup.+, 1 Br pattern.
EXAMPLE 25
Methyl 5-2-4-(4-pyridyl)piperazin-1-yl!acetyl!benzofuran-2-carboxylate
To a solution of 1-(4-pyridyl)piperazine (262 mg) and triethylamine (0.1
ml) in acetonitrile (10 ml) was added dropwise over 40 minutes a solution
of methyl 5-(2-bromoacetyl)benzofuran-2-carboxylate in acetonitrile (5
ml). The resulting mixture was stirred for 2 hours, concentrated and
purified by flash column chromatography on grade III alumina, eluting with
methanol/dichloromethane (1:99 to 4:96 v/v) to give the title compound as
a solid (138 mg); m.p. 173.degree.-177.degree. C., NMR 2.66(4H,m),
3.8(4H,m), 3.91(3H,s), 4.00(2H,s), 6.82(2H,m), 7.8.degree.-8.5(6H,m); m/e
380 (M+H.sup.+); calculated for C.sub.21 H.sub.21 N.sub.3 O.sub.4.
0.5H.sub.2 O: C, 64.9; H, 5.7; N, 10.8. Found: C, 65.2; H, 5.7; N, 10.9%.
The starting ester was prepared as follows:
i) Methyl 5-acetylbenzofuran-2-carboxylate
To a solution of 2-benzofuranoic acid methyl ester in carbon disulphide
(240 ml) cooled to 5.degree. C. was added acetyl chloride (70 ml) followed
portionwise over 1 hour by aluminium trichloride (40 g). The mixture was
heated under reflux for 42 hours before cooling and decanting the carbon
disulphide. The residual complex was destroyed by the addition of iced
water (50 ml) and 2N HCl (50 ml). The resulting mixture was extracted with
ethyl acetate (3.times.200 ml). The organic layers were combined, washed
with water (100 ml), dried (MgSO.sub.4) and concentrated. The residue was
purified by flash column chromatography, eluting with ethyl acetate/hexane
(10:90 to 40:60, v/v), to give methyl 5-acetylbenzofuran-2-carboxylate as
a solid (3.099 g); NMR 2.68(3H,s), 4.00(3H,s), 7.6-8.35(4H,m).
ii) Methyl 5-(2-bromoacetyl)benzofuran-2-carboxylate
To a suspension of cupric bromide (489 mg) in ethyl acetate (5 ml) at
reflux was added dropwise a solution of the product of step i) (272 mg) in
chloroform (5 ml) and the resulting mixture was refluxed for a further 3
hr. The resulting mixture was filtered, washed well with ethyl acetate and
then concentrated. The residue was purified by flash column
chromatography, eluting with ethyl acetate/hexane (20:80 v/v), to give
methyl 5-(2-bromoacetyl)benzofuran-2-carboxylate as a solid (247 mg); NMR
4.00(3H,s), 4.49(2H,s), 7.6-8.4(4H,m).
EXAMPLE 26
5-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!benzofuran-2-carboxylic acid
To a solution of the product of Example 25 (93 mg) in methanol (5 ml) was
added 1N sodium hydroxide (0.54 ml) and the resulting mixture was stirred
for 2 hours. The mixture was filtered and washed with methanol to give the
title compound as a solid (42 mg); NMR 2.66(4H,m), 3.29(4H,m), 3.97(2H,s),
6.78-7.01(3H,m), 7.58-8.33(5H,m); mn/e 366(M+H).sup.+ ; calculated for
C.sub.20 H.sub.19 N.sub.3 O.sub.4. 0.5H.sub.2 O C, 60.6; H, 4.8; N, 10.6;
Found: C, 60.4; H, 4.5; N, 10.2%.
EXAMPLE 27
Ethyl 1-2-4-(4-pyridyl)piperazin-1-yl!acetyl!piperidin-4-carboxylate
A solution of ethyl-1-(bromoacetyl)piperidin-4-carboxylate (0.84 g, 3
mMoles) in acetonitrile (10 ml) was added dropwise to a stirred solution
of 1-(4-pyridyl)piperazine (0.5 g, 3 mMoles) in acetonitrile (20 ml) and
the resulting mixture was allowed to stand for 3 hours. The white
precipitate was removed by filtration and the mother liquors were
concentrated under reduced pressure to give a yellow foam. The foam was
purified by chromatography (flash column made with grade III neutral
alumina and eluted with a gradient of 0-1% ethanol in dichloromethane) to
give the title compound (350 mg) as a colourless oil which was
crystallised from cyclohexane to give colourless prisms; mp
102.degree.-104.degree. C.; Microanalysis, found: C,63.5; H,8.1, N, 15.5%;
C.sub.19 H.sub.28 N.sub.4 O.sub.3 requires C,63.3; H,7.8; N,15.5%; NMR
(d.sub.6 DMSO + CD.sub.3 COOD): 1.2(t,3H), 1.3-1.7(m,2H), 1.8(m,2H),
2.5-2.8(m,6H), 3.0-3.4(m,3H), 3.6(brs,4H), 3.9(d, 1 H), 4.0(q,2H), 4.2(d,
I H), 7. I (d,2H), 8.2(d,2H); m/e 361 (M+H).sup.+.
The starting material was prepared as follows:
i) A solution of ethyl isonipecotatc (5.1 ml, 33 mMoles) in triethylaminie
(4.7 ml, 33 mMoles) was added dropwise to a stirred ice-cooled solution of
bromoacetyl bromide (2.9 ml, 33 mMoles) in ether (75 ml) and stirring was
continued for 1 hour. The resulting suspension was washed sequentially
with water (2.times.20 ml), dilute sodium bicarbonate solution (20 ml),
dilute citric acid solution (20 ml), water (20 ml) and saturated brine (30
ml), and then the organic fraction was dried (MgSO.sub.4) and concentrated
under reduced pressure to give ethyl
1-(bromoacetyl)piperidin-4-carboxylate (4.6 g) as a yellow oil which was
used without further purification; NMR (CDCl.sub.3) 1.2(t,3H),
1.6-2.1(m,4H), 2.5(m,1H), 2.9(m,1H), 3.2(m,1H), 3.8(s, 2H +m,IH),
4.15(q,2H), 4.3(m,1H); niCe 278/280 (M+H).sup.+.
EXAMPLE 28
1-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!piperidin-4-carboxylic acid
A solution of the product of Example 27 (200 mg, 0.56 mMoles) in dioxan (10
ml) and concentrated hydrochloric acid (5 ml) was heated on a steam bath
for 30 minutes. The solvent was evaporated under reduced pressure and the
residue was triturated with ether to give a foam. The foam was dissolved
in warm ethanol (lOmI), filtered and allowed to cool. The title compound
crystallised as colourless prisms (70 mg); mp 280.degree.-282.degree. C.
(dec); Microanalysis, found: C,50.0; H, 7.1; N,12.7; Cl,16.4; H.sub.2 O,
2.5%; C.sub.17 H.sub.24 N.sub.4 O.sub.3.2HCl.0.5H.sub.2 O. 0.33C.sub.2
H.sub.6 O requires: C,49.4; H,6.8; N,13.0; Cl,16.5; H.sub.2 O, 2.1%; NMR
(d.sub.6 DMSO+ CD.sub.3 COOD) 1.4-1.7(m,2H), 2.0(m,2H), 2.9(t,iH),
3.2(t,IH), 3.4-3.7(m,5H), 3.9-4.2(brs,4H), 4.3(d,1), 4.4(q,2H),
7.25(d,2H), 8.3(d,2H), + signals due to ethanol (0.33 Mole eq) m/e 333
(M+H).sup.+.
EXAMPLE 29
Ethyl 2-1-2-4-(4-pyridyl)piperazin-1-yl!acetyl!piperidin-4-yl!acetate
A solution containing 1-(4-pyridyl)-4-carboxymethylpiperazine
dihydrochloride 1/4H.sub.2 O(400 mg, 1.33 mMoles), triethylamine (0.4 ml,
2.66 mMoles) and HOBT (0.2 g, 1.46 mMoles) in dry dimethylformamide (20
ml) was treated with diisopropylcarbodiimide (0.23 ml 1.46 mMoles) and the
mixture was stirred for 5 minutes. Ethyl 4-carboxymethylpiperidine was
added and the mixture was stirred for a further 4 hours. The mixture was
concentrated to half volume under reduced pressure and then poured into
water (50 ml) and extracted with ethyl acetate (3.times.20 ml) and
dichloromethane (3.times.20 ml). The combined organic extracts were
concentrated under reduced pressure and the residue was purified by
chromatography (flash column made with grade III alumina and eluted with a
gradient of 0-1% methanol in dichloromethane) to give the title compound
(130 mg) as a colourless oil; NMR (d.sub.6 DMSO) 0.9-1.1 (m,2H),
1.2(t,3H), 1.65(d,2H), 1.8-2.0(m,1H), 2.2(d,2H), 2.5(m,2H),
2.9-3.4(m,10H), 4.0(q,2H +m,1H), 4.3(d,1H), 6.8(d,2H ), 8.15(d,2H); m/e
375 (M+H).sup.+.
The starting materials were prepared as follows:
i) 1-(4-Pyridyl)-4-carboxymethylpiperazine, hydrochloride
A solution of tert-butyl bromoacetate (1.0 ml, 6.1 mMoles) in acetonitrile
(20 ml) was added to a stirred solution of 1-(4-pyridyl)-piperazine (2.0
g, 12.3 mMoles) in acetonitrile (30 ml) and the mixture was stirred for 4
hours. The white precipitate was removed by filtration and the filtrate
was concentrated under reduced pressure to give a yellow foam. The foam
was purified by chromatography (flash column made with grade III alumina
and eluted with a gradient of 0-1% methanol in dichloromethane) to give a
colourless crystalline solid (900 mg). Recrystallisation from cyclohexane
gave tert-butyl 1-(4-pyiidyl)piperazine-4-acetic ester (500 mg) as
coloulless prisms; mp 83.degree.-85.degree. C.; Microanalysis, found:
C,65.2; H,8.6; N,15.0; C.sub.15 H.sub.23 N.sub.3 O.sub.2 requires: C,65.0;
H,8.4; N,15.1%; NMR (d.sub.6 DMSO) 1.4(s,9H), 2.6(t,4H), 3.2(s,2H),
3.5(t,4H), 6.8(d,2H), 8.15(d,2H); m/e 278 (M+H).sup.+.
A solution of tert-butyl1-(4-pyridyl)piperazine-4-acetic ester (400 mg, 1.4
mMoles) in concentrated hydrochloric acid (10 ml) was allowed to stand for
1.5 hours and was then concentrated under reduced pressure. The residue
was triturated with hot acetone, filtered and washed with acetone to give
1-(4-pyridyl)-4-carboxymethylpiperazine, hydrochloride (350 mg) as a pale
cream solid; Microanalysis, found: C,44.2; H,5.9; N,13.8; Cl,23.8; H.sub.2
O,1.4%; C.sub.11 H.sub.15 N.sub.3 O.sub.2.2HCl.0.25H.sub.2 O requires:
C,44.2; H,5.9; N,14.1; Cl,23.7; H.sub.2 O,1.3%; NMR (d.sub.6 DMSO)
3.4-3.6(brs,4H), 4.0-4.2(brs,4H), 4.2(s,2H), 7.3(d,2H), 8.4(d,2H); m/e 222
(M+H).sup.+.
ii) Ethyl-4-carboxymethylpiperidine
A stirred suspension of sodium hydride (50% dispersion in mineral oil, 4.8
g, 0.1 Moles) in dimethoxyethane (300 ml) was ice-cooled and treated under
an atmosphere of argon with triethyl phosphonoacetate (19.82 ml, 0.1
Moles), added dropwise. Stirring was continued for 1 hour during which
time the temperature of the mixture was maintained <5.degree. C. The
cooling bath was removed and N-benzylpiperidone (17.85 ml, 0.1 Moles) was
added dropwise. The mixture was stirred overnight at room temperature,
then diluted with water (500 ml) and extracted with ether (3.times.200
ml). The combined organic extracts were washed with water (200 ml) and
saturated brine (100 ml), dried (MgSO4) and concentrated under reduced
pressure. The residue was purified by chromatography (flash column, eluted
with hexane/ethyl acetate; 3:2) to give ethyl
4-carboxymethylene-N-benzylpiperidine ester (5.52 g) as a yellow oil; NMR
(CDCl.sub.3) 1.1 (t,3H), 2.2(t,2H), 2.4(m,4H), 3.4(s,2H), 4.0(q,2H),
5.6(s,1H), 7.2(m,5H); m/e 260 (M+H).sup.+.
A solution of ethyl 4-carboxymethylene-N-benzylpiperidine ester (5.5 g, 21
mMoles) in ethanol (250 ml was stirred with 10% palladium on carbon under
an atmosphere of hydrogen until a total of 950 ml of hydrogen had been
consumed. An additional quantity of 10% palladium on carbon (500 mg) was
added and stirring was continued for 4 hours to remove residual starting
material. The mixture was filtered and concentrated under reduced pressure
to give ethyl 4-carboxymethylpiperidine ester (3.31 g) as a slightly green
oil which was used without further purification; NMR (CDCl.sub.3)
1.0-1.2(m,2H), 1.25(t,3H), 1.7(s,2H), 1.9(m,1H), 2.2(d,2H), 2.6(td,2H),
3.05(dt,2H), 4.0(q,2H); m/e 172 (M+H).sup.+.
EXAMPLE 30
2-1-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!piperidin-4-yl!acetic acid
In a similar manner to Example 28, but starting from the product of Example
29, the title compound was prepared as colourless prisms from isopropanol;
mp 248.degree.-250.degree. C. (decomposition); Microanalysis, found:
C,50.2; H,6.8; N,12.6; H.sub.2 O,3.4%; C.sub.18 H.sub.26 N.sub.4
O.sub.3.2HCl.0.8H.sub.2 O requires: C,49.8; H,6.9; N12.9; H.sub.2 O, 3.3%;
NMR (d.sub.6 DMSO+ CD.sub.3 COOD) 0.9-1.3(m,2H), 1.7(m,2H), 1.9(m,1IH),
2.2(d,2H), 2.7(t,1 H), 3.15(t,1H), 3.4-3.7(m,5H), 3.8-4.2(m,4H),
4.3-4.5(m,3H), 7.2(d,2H), 8.3(d,2H); m/e 347 (M+H).sup.+.
EXAMPLE 31
Tert-butyl
2-1-2-4-(4-pyridyl)piperazin-1-yl!acetyl!piperidin-4-yloxy!acetate
A solution of 1-(4-pyridyl)-carboxymethylpiperidine (400 mg, 1.33 mMoles)
triethylamine (0.4 ml, 2.66 mMoles) and HOBT (0.2 g, 1.46 mMoles) in dry
dimethylformamide (20 ml) was treated with diisopropylcarbodiimide (0.23
ml, 1.46 mMoles) and the mixture was stirred for 5 minutes. Tert-butyl
piperidine-4-oxyacetic ester (614 mg, 2.8 mMoles) was added and the
mixture was stirred for a further 6 hours. The mixture was concentrated to
half volume under reduced pressure and then poured into water (50 ml) and
extracted with dichloromethane (4.times.30 ml). The combined organic
extracts were washed with saturated brine and concentrated under reduced
pressure. The residue was purified by chromatography (flash column made
with grade III alumina and eluted with a gradient of 0-1% methanol in
dichloromethane) to give the title compound (240 mg) as a colourless oil;
NMR (d.sub.6 DMSO) 1.3-1.7(m,2H +s,9H), 1.7-1.9(m,2H), 3.0-3.5(m,12H),
3.55(m, 1H), 3.8(m,2H), 4.0(s,2H), 6.8(d,2H), 8.15(d,2H); m/e 419
(M+H).sup.+.
The starting material was prepared as follows:
i) An ice-cooled solution containing 4-piperidiniol (5 g, 50 mMoles) and
triethylamine (7 ml, 50 mMoles) in dichloromethane (50 ml) was cautiously
treated with benzylchloroformate (7.5 ml, 50 mMoles) and allowed to stir
for 2 hours. Dichloromethane (25 ml) was added and the solution was washed
sequentially with water (2.times.40 ml) and saturated brine (50 ml), then
dried (MgSO4) and concentrated under reduced pressure. The residue was
purified by vacuum flash chromatography, eluting with a gradient of
50-100% ether in hexane to give N-benzyloxycarbonyl piperidin-4-ol (7.5 g)
as a colourless oil; NMR (d.sub.6 DMSO) 1.2-1.4(m,2H), 1.6-1.8(m,2H),
3.0-3.2(m,2H), 3.6-3.8(m,3H), 4.7(d,2H), 5.1(2,2H), 7.3(m,5H); m/e 236
(M+H).sup.+.
A solution of N-benzyloxycarbonyl piperidin-4-ol (7 g, 30 mMoles) in dry
THF (100 ml) was treated with sodium hydride (60% suspension in mineral
oil, 1.3 g, 32 mMoles) and the resulting mixture was stirred until
effervescence ceased (about 1 hour). Tert-butylbromoacetate (5.1 ml, 32
mMoles) was added and stirring was continued for a further 2 hours. The
mixture was diluted with ether (200 ml), washed with water (3.times.75 ml)
and saturated brine (75 ml), dried (MgSO4) and concentrated under reduced
pressure. The residual oil was purified by chromatography (flash column
eluted first with hexane/ether 1:1 and then with ether alone) to give
tert-butyl N-benzyloxycarbonyl-piperidine-4-oxyacetic ester (3.0 g) as a
colourless oil; NMR (d.sub.6 DMSO) 1.3-1.5(m,2H +s,9H), 1.7-1.9(m,2H),
3.0-3.2(m,2H), 3.5-3.8(m,3H), 4.0(s,2H), 5.1(s,2H), 7.35(m,5H); m/e 350
(M+H).sup.+.
A solution of tert-butyl N-benzyloxycarbonylpiperidine-4-oxyacetic ester
(1.0 g, 2.9 mMoles) in iso-propanol (40 ml) was stirred with charcoal,
filtered and stirred with 10% palladium on carbon (200 mg) under an
atmosphere of hydrogen. When 50 ml of hydrogen had been consumed the
mixture was filtered and the filtrate was concentrated under reduced
pressure to give tert-butyl piperidine-4-oxyacetic ester (614 mg) as a
colourless oil which was used without further purification.
EXAMPLE 32
2-1-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!piperidin-4-yloxy!acetic acid
A solution of the product of Example 31 (220 mg, 0.53 mMoles) in a mixture
of dichloromethane (5 ml) and trifluoroacetic acid (5 ml) was allowed to
stand for 1.5 hours and was then concentrated under reduced pressure. The
residue was triturated with ether and crystallised from isopropanol (12
ml) to give the title compound (200 mg) as colourless prisms; mp
198.degree.-200.degree. C.; Microanalysis, found: C,45.0; H,4.8; N,9.4%;
C.sub.18 H.sub.26 N.sub.4 O.sub.4.2CF.sub.3 COOH requires: C,44.8; H,4.8;
N,9.5%; NMR (d.sub.6 DMSO) 1.3-1.7(m,2H), 1.8-2.0(m,2H), 3.0-4.2(m, 16H),
4.15(s,2H), 7.25(d,2H), 8.3(d,2H); m/e 363 (M+H).sup.+.
EXAMPLE 33
Methyl
2-S-(n-butylsulphonylamino)-3-4-1-(4-pyridyl)piperidin-4-yl!methoxypheny
l!propionate
n-Butylsulphonyl chloride (0.32 ml) was added dropwise to a solution of
methyl
2-Samino-3-4-(1-(4-pyridyl)piperidin-4-yl)methoxyphenyl!-propionate (750
mg) and triethylamine (0.5 ml) in dichloromethane (15 ml) cooled in an ice
bath. The mixture was allowed to reach ambient temperature and stirred for
5 hours and then refluxed for 2 hours. The reaction mixture was washed
with water (20 ml) and saturated sodium chloride solution (15 ml) and
dried (MgSO.sub.4). The solvent was evaporated and the residue purified by
flash chromatography eluting with methanol/dichloromethane (1.9 v/v) to
give the title compound (650 mg) as a gum; NMR(CDCl.sub.3) 0.87(t,3H),
1.26-1.7(m,6H), 1.95(d,2H), 2.1(m, 1H), 2.72-3.18(m,6H), 3.77(s,3H),
3.79(d,2H), 3.96(d,2H), 4.32(m,1H), 4.82(brd,1H), 6.69(d,2H), 6.83(d,2H),
7.1(d,2H), 8.25(brd,2H); mass spectrum (+ve FAB MeOH/NBA): 490 (M+H).sup.+
.alpha.!.sub.D.sup.22 =14.degree. C. (c=1, MeOH).
The starting material was prepared as follows:
i) Diethylazodicarboxylate (0.58 ml) was added dropwise to a stirred
mixture of 4-(4-hydroxymethylpiperidin-1-yl)pyridine (700 mg),
N-benzyloxycarbonyl-S-tyrosine methyl ester (1.2 g), triphenylphosphine
(955 mg) and THF (40 ml) in an atmosphere of argon and cooled to
10.degree. C. The mixture was allowed to reach ambient temperature and
stirred for 48 hours. The solvent was removed by evaporation and the
residue purified by flash chromatography eluting with
methanol/dichloromethane (1:9 v/v) to give methyl
2S-(benzyloxycarbonylamino)-3-4-(1-(4-pyridyl)piperidin-4-yl)methoxypheny
l!propionate (1.2 g) as a solid m.p. 68.degree.-75.degree. C.; NMR(d.sub.6
DMSO) 1.2-1.4(m,2H), 1.84(d,d,2H), 1.92-2.1(m, 1H), 2.7-3.02(m,4H),
3.6(s,3H), 3.8(d,2H), 3.98(d,2H), 4.14-4.28(m, 1H), 4.98(s,2H),
6.78-6.88(m,4H), 7.13(d,2H), 7.20-7.4(m,5H), 7.75(d,1H), 8.13(d,2H); mass
spectrum (+ve FAB, MeOH/NBA): 504(M+H).sup.+.
ii) A solution of the product of step i) (1 g) in ethanol (40 ml) and 10%
palladium/carbon (200 mg) was stirred in a stream of hydrogen for 4 hours
at ambient temperature. The mixture was filtered through a pad of
diatomaceous earth and the solvent removed by evaporation to give methyl
2-S-amino-3-4-(1-(4'-pyridyl)piperidin-4-yl)methoxyphenyl!propionate as
an oil; NMR(d.sub.6 DMSO) 1.13-1.44(m,2H), 1.75-2.13(m,3H),
2.64-2.94(m,4H), 3.51(m,1H), 3.57(s,3H), 3.81(d,2H), 3.96(d,2H),
6.8(dd,2H), 6.83(d,2H), 7.08(d,2H), 8.12(dd,2H); mass spectrum(+ve FAB,
MeOH/NBA): 370 (M+H).sup.+.
EXAMPLE 34
2-S-(n-Butylsulphonylamino)-3-4-1-(4-pyridyl)piperidin-4-yl!methoxyphenyl
!propionic acid
Lithium hydroxide (285 mg) was added to a solution of the product of
Example 33 (520 mg) in a mixture of methanol (9 ml), THF (9 ml) and water
(9 ml) and stirred at ambient temperature for 3.75 hours. The solvent was
evaporated and water (5 ml) added to the residue. A 10% aqueous solution
of potassium hydrogen sulphate (8 ml) was added and an oil separated. The
oil was dissolved in methanol and filtered through diatomaceous earth. The
solvent was evaporated, and the residue triturated with ethyl acetate gave
the title compound (500 mg) as an amorphous solid, NMR (d.sub.6 DMSO)
0.81(t,3H), 1.1-1.6(m,6H), 1.85(d,2H), 2.0(brs, 1H), 2.58-3.0(m,6H),
3.68(t,2H), 3.8(d,2H), 3.98(d,2H), 6.8(brs,4H), 7.13(d,2H), 8.12(brs,2H);
mass spectrum(+ve FAB, MeOH/NBA): 476(M+H).sup.+.
EXAMPLE 35
Methyl
2-S-(n-butylsulphonylamino)-3-4-2-1-(4-pyridyl)piperidin-4-yl!ethoxy!ph
enyl!propionate
n-Butylsulphonyl chloride (0.28 ml) was added dropwise to a solution of
methyl
2-S-amino-3-4-2-1-(4-pyridyl)piperidin-4-yl!ethoxy!phenyl!propionate
(630 mg) and triethylamine (0.5 ml) in dichloromethane (15 ml) cooled in
an ice-bath. The mixture was allowed to reach ambient temperature and
stirred for 5 hours. The reaction mixture was diluted with dichloromethane
(10 ml) and washed with water (20 ml), saturated sodium chloride solution
(10 ml) and dried (MgSO.sub.4). The solvent was evaporated and the residue
purified by flash chromatography eluting with methanol/dichloromethane(1:9
v/v) to give the title compound (680 mg) as a gum; NMR (CDCl.sub.3)
0.9(t,3H), 1.25-1.45(m,4H), 1.55-1.95(m,7H), 2.72-3.15(m,6H), 3.78(s,3H).,
3.9(brd,2H), 4.0(t,2H), 4.32(brs,1H), 4.84(brs, 1 H), 6.68(d,2H),
6.83(d,2H), 7.09(d,2H), 8.23(brs,2H): mass spectrum(+ve FAB, MeOH/NBA):
504 (M+H).sup.+.
The starting material was prepared as follows:
i) Following the method of Example 33i) but using
4-(4-hydroxyethylpiperidin-1-yl)pyridine, methyl
2-S-(benzyloxycarbonylamino)-3-4-2-1-(4-pyridyl)piperidin-4-yl!ethoxy!p
henyl!propionate (900 mg) was prepared as an oil; NMR (d.sub.6 DMSO)
1.05-1.35(m,2H), 1.6-1.9(m,5H), 2.7-3.05(m,4H), 3.63(s,3H), 3.92(d,2H),
4.0(t,2H), 4.21(m,1H), 4.98(s,2H), 6.8(d,2H), 6.84(d,2H), 7.14(d,2H),
7.3(m,4H), 7.75(d, 1H), 8.12(d,2H); mass spectrum(+ve FAB, NBA/CH.sub.2
Cl.sub.2): 518 (M+H).sup.+.
ii) Following the method of Example 33ii), but using the product of step i)
above, methyl 2-S-amino-3-4-2-1
-(4-pyridyl)piperidin-4-yl!ethoxy!phenyl!propionate was prepared as a gum;
NMR (d.sub.6 DMSO) 1.08-1.32(m,2H), 1.58-1.86(m,5H), 2.61-2.9(m,4H),
3.52(m,1H), 3.58(s,3H), 3.82-4.02(m,4H), 6.79(dd,2H), 6.81(d,2H),
7.07(d,2H), 8.1(dd,2H); mass spectrum(+ve FAB, MeOH/NBA): 384 (M+H).sup.+.
EXAMPLE 36
2-S-(n-Butylsulphonylamino)-3-4-2-1-(4-pyridyl)piperidin-4-yl!ethoxy!phe
nyl!propionic acid
Following the method of Example 34, but using the product of Example 35 the
title compound (380 mg) was prepared; NMR (d.sub.6 DMSO) 0.78(t,3H),
1.05-1.5(m,6H), 1.6-1.9(m,5H), 2.5-3.05(m,6H), 3.8-4.05(m,6H), 4.6(brs,
1H), 6.85(m,4H), 7.19(d,2H), 8.13(brs,2H); mass spectrum(+ve FAB,
MeOH/NBA): 490 (M+H).sup.+ ; microanalysis found: C, 57.7; H, 7.5; N, 8.0;
H.sub.2 O, 7.1%; C.sub.25 H.sub.35 N.sub.3 O.sub.5 S.2H.sub.2 O requires:
C, 57.1; H, 7.4; N, 8.0; H.sub.2 O, 6.9%.
EXAMPLE 37
Methyl
2-S-(n-butylsulphonylamino)-3-4-1-(4-pyridyl)piperidin-4-yl!oxyphenyl!pr
opionate
Using a procedure similar to that described in Example 35, but starting
from the appropriate amino acid ester, the title compound was prepared NMR
(CDCl.sub.3) 0.9(t,3H), 1.25-1.45(m,2H), 1.55-1.8(m,2H), 1.8-2.15(m,4H),
2.6-2.88(m,2H), 2.9-3.2(m,2H), 3.3-3.45(m,2H), 3.55-3.74(m,2H),
3.78(s,3H), 4.27-4.4(m, 1H), 4.45-4.6(m,1 H), 4.8(brd,2H), 6.7(d,2H),
6.86(d,2H), 7.1(d,2H), 8.26(brd,2H); mass spectrum (+ve FAB, MeOH/NBA):
476 (M+H).sup.+.
The starting material was prepared using similar procedures to those
described in Example 35. There were thus prepared the following
intermediates starting from 4-(4-hydroxypiperidin-1-yl)pyridine:
Methyl 2-S-(benzyloxycarbonylamino)-3-4-(1-(4'-
pyridyl)piperidin-4-yl)oxyphenyl!propionate; NMR (d.sub.6 DMSO)
1.5-1.72(m,2H), 1.9-2.1 (m,2H), 2.7-3.02(m,2H), 3.18(d,2H),
3.2-3.35(m,1H), 3.48-3.77(m, 1H), 3.62(s,3H), 4.13-4.28(m, 1H),
4.5-4.65(m,1H), 4.97(s,2H), 6.8-6.94(m,4H), 7.14(d,2H), 7.77(d,1H),
8.15(d,2H); mass spectrum(+ve FAB, CH.sub.2 Cl.sub.2 /NBA): 518
(M+H).sup.+.
Methyl 2-S-amino-3-4-(1-(4'-pyridyl)piperidin-4- yl)oxyphenyl!propionate;
NMR (d.sub.6 DMSO): 1.54-1.72(m,2H), 1.9-2.06(m,2H), 2.65-2.88(m,2H),
3.15-3.4(m,2H), 3.52(t,1H), 3.59(s,3H), 3.6-3.75(m,2H), 4.52-4.65(m,1H),
6.8-6.92(m,4H), 7.09(d,2H), 8.15(dd,2H); mass spectrum (+ve FAB,
MeOH/NBA): 356 (M+H).sup.+.
EXAMPLE 38
2-S-(n-Butylsulphonylamino)-3-4-1-(4-pyridyl)piperidin-4-yl!oxyphenyl!pro
pionic acid
Using a similar procedure to that described in Example 34 but startinig
from the product of Example 37, the title compound was obtaincd as a solid
m.p.255.degree.-258.degree. C. dec.; NMR (d.sub.6 DMSO) 0.66(t,3H),
0.98-1.04(m,2H), 1.05-1.4(m,2H), 1.44-1.62(m,2H), 1.8-1.96(m,2H),
2.49(t,2H), 2.61(dd,1H), 2.87(dd,1H), 3.12-3.28(m,2H), 3.4-4.0(m,5H),
4.43-4.55(m, 1H), 6.79(m,4H), 7.09(d,2H), 8.04(brd,2H); mass spectrum(+ve
FAB, MeOH/NBA): 462 (M+H).sup.+ ; microanalysis found: C, 59.6; H 6.9; N,
9.0%; C.sub.23 H.sub.31 N.sub.3 O.sub.5 S requires: C, 59.8; H, 6.8; N,
9.1%.
EXAMPLE 39
N-N-2-4-(4-Pyridyl)piperazin-1-yl!acetal!-L-aspartyl!-L-phenylalanine
To a solution of
O-benzyl-N-O-benzyl-N-2-4-(4-pyridyl)piperazin-1-yl!acetyl!-L-aspartyl!
-L-phenylalanine (0.92 g) in methanol (125 ml) under argon was added 10% Pd
on C (0.45 g). The mixture was covered with a blanket of hydrogen and
stirred at room temperature until deprotection was complete. The catalyst
was filtered off through a pad of kieselguhr and the filtrate was
evaporated to dryness. The resultant white solid was dissolved in water
and lyophilised overnight to yield the title compound (274 mg) as a white
solid: m.p. 153.degree. C. (dec); NMR (d.sub.6 DMSO +CD.sub.3 CO.sub.2 D)
.delta. 2.65(6H,m), 3.02(4H,m), 3.63(4H,m), 4.44(1H,m), 4.67(1H,m),
7.13(2H,d), 7.23(5H,m), 8.22(2H,d); m/Z484 (M+H).sup.+ ; calculated for
C.sub.24 H.sub.29 N.sub.5 O.sub.6.m/Z 484 (M+H).sup.+ ; amino acid
analysis: found; Asp, 1.00; Phe 0.99; requires; Asp, 1.00; Phe, 1.00.
The starting matcrial was prepared as follows:
i) Boc-L-Asp(OBzl)-L-Phe-OBzl (9.91 g) was dissolved in a mixture of
trifluoroacetic acid (50 ml) and dichloromethanie (50 ml). The resultant
solution was stored at room temperature for 2 hr. The reaction mixture was
evaporated to dryness to yield a residue which was triturated with ether,
collected, washed thoroughly with ether and dried under high vacuum to
yield L-Asp(OBzl)-L-Phe-OBzl, trifluoroacetate salt (8.36 g) as a white
solid: NMR (CDCl.sub.3) .delta. 2.88(2H,m), 3.07(2H,m), 4.33(1H,m),
4.78(1H,m), 5.02(2H,s), 5.06(2H,q), 6.20(3H,vbr), 7.04(2H,m), 7.26(13H,m),
7.65(1H,d); m/Z 461 (M+H).sup.+.
ii) To an ice-cold solution of 1-(4-pyridyl)-4-carboxymethylpiperazine
dihydrochloride (307 mg), HOBt.H.sub.2 O (176 mg) and HBTU (436 mg) in DMF
(8 ml) under argon was added diisopropylethylamine (1.07 ml), followed,
after 5 minutes, by a solution of the product of step (i) (600 mg) in DMF
(5 ml). The reaction mixture was allowed to warm to room temperature with
stirring overnight under argon. The reaction mixture was diluted with
ethyl acetate (100 ml) and washed with water, dilute KHSO.sub.4 (aq.),
dilute NaHCO.sub.3 (aq.), water, dried (MgSO.sub.4) and evaporated to
yield O-benzyl-N-O-benzyl-N-2-4-(4-pyridyl)piperazin-1-yl!acetyl!-L-asp
artyl!-L-phenylalanine (690 mg) as an off-white amorphous solid: NMR
(d.sub.6 DMSO+CD.sub.3 CO.sub.2 D) .delta. 2.50(4H,m), 2.69(2H,m),
2.96(4H,m), 3.54(4H,m), 4.52(1H,m), 4.72(1H,m), 5.00(4H,s), 7.03(2H,d),
7.23(15H,m), 8.10(2H,m); m/Z 664 (M+H).sup.+.
EXAMPLE 40
N-N-N-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!glycyl!-L-aspartyl!-L-phenyla
lanine
In a similar manner to Example 39,
O-benzyl-N-O-benzyl-N-N-2-4-(4-pyridyl)piperazin-1-yl!acetyl!glycyl!-L-
aspartyl!-L-phenyl-alanine (0.42 g), 10% Pd on C (200 mg) and methanol (125
ml) under a blanket of hydrogen gave, after lyophilisation from water, the
title compound (91 mg) as a white solid: m.p. 180.degree. C. (dec); NMR
(d.sub.6 DMSO+CD.sub.3 CO.sub.2 D) .delta. 2.50(l1H,m), 2.67(5H,m),
2.96(1H,m), 3.10(3H,m), 3.72(4H,m), 3.82(2H,s), 4.44(1H,m), 4.64(1H,m),
7.13(2H,d), 7.23(5H,m), 8.18(2H,d); m/Z 541 (M+H).sup.+ ; amino acid
analysis: found; Asp, 1.00; Phe 1.04; Gly, 0.98; requires; Asp, 1.00; Phe,
1.00; Gly, 0.98.
The starting material was prepared as follows:
i) In a similar manner to Example 39ii), Boc-Gly-OH (1.28 g), HOBt.H.sub.2
O (1.23 g), HBTU (3.04 g), diisopropylethylamine (5 ml),
L-Asp(OBzl)-L-Phe-OBzl, trifluoroacetate salt (4.18 g) and DMF (40 ml)
gave Boc-Gly-L-Asp(OBzl)-L-Phe-OBzl (4.4 g) as a white solid: NMR
(CDCl.sub.3) .delta. 1.47(9H,s), 2.63(1H,m), 3.08(3H,m), 3.69(2H,m),
4.80(2H,m), 5.10(2H,s), 5.13(2H,q), 6.97(1H,d), 7.05(2H,m), 7.28(13H,m);
m/Z 618 (M+H).sup.+.
ii) In a similar manner to Example 39i), the product of step i) (5.6 g),
trifluoroacetic acid (30 ml) and dichloromethane (30 ml) gave
Gly-L-Asp(OBzl)-L-Phe-OBzl, trifluoroacetate salt (5.6 g) as a colourless
oil: NMR (CDCl.sub.3 +CD.sub.3 CO.sub.2 D) .delta. 2.80(2H,m), 3.09(2H,m),
3.85(2H,s), 4.83(1H,m), 4.93(1H,m), 5.07(2H,s), 5.10(2H,q), 7.05(2H,m),
7.25 (13H,m); m/Z 5 18 (M+H).sup.+.
iii) In a similar manner to Example 39ii),
1-(4-pyridyl)-4-carboxymethylpiperaziine dihydrochloride (280 mg),
HOBt.H.sub.2 O (160 mg), HBTU (400 mg), diisopropylethylamine (0.98 ml),
the product of step (ii) (600 mg) and DMF (10 ml) gave
O-benzyl-N-O-benzyl-N- N-2-
4-(4-pyridyl)piperazin-1-yl!acetyl!glycyl!-L-aspartyl!-L-phenylalanine
(0.42 g) as an off-white solid: NMR (CDCl.sub.3) .delta. 2.68(5H,m),
3.10(5H,m), 3.49 (4H,m), 3.93(2H,d), 4.81(2H,m), 5.09(2H,s), 5.10(2H,q),
6.74(2H,d), 7.07(2H,m), 7.25(15H,m), 7.64(1H,t), 8.18(2H,d); m/Z 721
(M+H).sup.+.
EXAMPLE 41
Methyl 4-2-4-(2-methyl-4-quinolinyl)piperazin-1-yl!acetyl!phenoxyacetate
In a similar manner to Example 1, methyl 4-bromoacetylphenoxyacetate (1.62
g), 2-methyl-4-(1-piperazinyl)quinoline (preparation described in Sharma,
M. et al (1981), Pol. J. Pharmacol. Pharm. 33(5), 539-44) (2.59 g) and
acetonitrile (80 ml) yielded, after stirring at room temperature
overnight, filtration and evaporation of the filtrate, an orange/brown
oily residue which was purified by flash chromatography, first on neutral
alumina by elution with 3% v/v methanol/dichloromethane, then on silica by
elution with methanol/dichloromethane (0.5% v/v to 3% v/v), and finally by
crystallisation from methanol/water, to yield the title compound (671 mg)
as an off-white solid: NMR (CDCl.sub.3) .delta. 2.68(3H,s), 2.92(4H,m),
3.32(4H,m), 3.83(3H,s), 3.90(2H,s), 4.73(2H,s), 6.74(1H,s), 6.97(2H,d),
7.42(1H,m), 7.63(1H,m), 7.98(2H,m), 8.06(2H,d); m/Z 434 (M+H).sup.+ ;
calculated for C.sub.25 H.sub.27 N.sub.3 O.sub.4 : C, 69.3%; H, 6.28%; N,
9.69%; found: C, 69.2%; H,6.4%; N, 9.6%.
EXAMPLE 42
4-2-4-(2-Methyl-4-quinolinyl)piperazin-1-yl!acetyl!phenoxyacetic acid
A mixture of the product of Example 41 (100 mg) and 0.5% v/v
triethylamine/water (20 ml) was stirred at room temperature overnight, by
which time all of the solids had dissolved. The pale yellow solution was
washed with ether, filtered and lyophilised overnight to yield the title
compound (107 mg) as an off-white solid: NMR (d.sub.6 DMSO) .delta.
1.13(2.7H,t), 2.58(3H,s), 2.83(4H,m), 2.97(1.8H,q), 3.18(4H,m),
3.88(2H,s), 4.70(2H,s), 6.87(1H,s), 6.99(2H,d), 7.45(1H,m), 7.63(1H,m),
7.83(1H,m), 7.94(1H,m), 8.01(2H,d); m/Z 420 (M+H).sup.+ ; calculated for
C.sub.24 H.sub.25 N.sub.3 O.sub.4.0.3 Et.sub.3 N. 1H.sub.2 O: C, 66.2%; H,
6.79%; N, 9.88%; found: C, 65.9%; H, 6.7%; N, 9.6%.
EXAMPLE 43
Methyl 4-2-4-(4-quinolinyl)piperazin-1-yl!acetyl!phenoxyacetate
In a similar manner to Example 1, methyl 4-bromoacetylphenoxyacetate (1.60
g), 4-(1-piperazinyl)quinoline (Preparation described in EP 281309 A1)
(2.39 g) and acetonitrile (75 ml) yielded, after stirring at room
temperature overnight, filtration and evaporation of the filtrate, an
orange/brown oily residue which was purified by flash chromatography,
first on neutral alumina by elution with 3% v/v methanol/dichloromethane,
then on silica by elution with methanol/dichloromethane (0.5% v/v to 5%
v/v), and finally by crystallisation from methanol/water, to yield the
title compound (373 mg) as a yellow solid: NMR (CDCl.sub.3) .delta.
2.91(4H,m), 3.33(4H,m), 3.82(3H,s), 3.89(2H,s), 4.72(2H,s), 6.86(1H,d),
6.96(2H,d), 7.48(1H,m), 7.65(1H,m), 8.02(2H,m), 8.06(2H,d), 8.73(1 H,d);
m/Z 420 (M+H).sup.+ ; calculated for C.sub.24 H.sub.25 N.sub.3
O.sub.4.0.25 H.sub.2 O: C, 68.0%; H, 6.06%; N, 9.91%; found: C, 67.9%; H,
6.0%; N, 9.7%.
EXAMPLE 44
4-2-4-(4-Quinolinyl)piperazin-1-yl!acetyl!phenoxyacetic acid
trifluoroacetate salt
In a similar manner to Example 42, the product of Example 43 (313 mg), and
1% v/v triethylamine/water (65 ml) gave, after 2 days stirring at room
temperature, washing with ether, filtration and lyophilisation, an
off-white solid which was purified by preparative rp-hplc on a DYNAMAX
C-18, 60A 83-201-C! column using an acetonitrile/water mobile phase
system containing 0.1% trifluoroacetic acid, to give, after
lyophilisation, the title compound (200 mg) as a white solid: NMR (d.sub.6
DMSO) .delta. 3.45(4H,m), 3.99(4H,m), 4.85(4H,s), 7.13(2H,d), 7.32(1H,d),
7.74(1 H,m), 8.01(4H,m), 8.19(1H,m), 8.83(1H,d); m/Z 406 (M+H).sup.+ ;
calculated for C.sub.23 H.sub.23 N.sub.3 O.sub.4.2.0 CF.sub.3 CO.sub.2 H:
C, 51.2%; H, 3.98%; N, 6.63%; found: C, 50.9%; H, 3.9%; N, 6.5%.
EXAMPLE 45
Methyl
4-2-4-(5,6,7,8-tetrahydro-4-quinolinyl)piperazin-1-yl!-acetyl!phenoxyace
tate
In a similar manner to Example 1, methyl 4-bromoacetylphenoxyacetate (1.23
g), a 1:1 mixture containing 4-(1-piperazinyl)quinoline and
4-(1-piperazinyl)-5,6,7,8-tetrahydroquinoline (1.84 g) and acetonitrile
(56 ml) yielded, after stirring at room temperature overnight, filtration
and evaporation of the filtrate, an orange/brown oily residue which was
purified by flash chromatography, first on neutral alumina by elution with
5% v/v methanol/dichloromethane, then on silica by elution with
methanol/dichloromethane (0.5% v/v to 5% v/v), and finally by
crystallisation of the lower Rf material from methanol/water, to yield the
title compound (298 mg) as a cream solid: NMR (CDCl.sub.3) .delta.
1.76(2H,m), 1.89(2H,m), 2.64(2H,m), 2.76(4H,m), 2.95(2H,m), 3.07(4H,m),
3.80(2H,s), 3.81(3H,s), 4.71(2H,s), 6.68(1H,d), 6.95(2H,d), 8.03(2H,d),
8.28(1H,d); m/Z 424 (M+H).sup.+ ; calculated for C.sub.24 H.sub.29 N.sub.3
O.sub.4.1.0 H.sub.2 O: C, 65.3%; H, 7.08%; N, 9.52%; found: C, 65.6%; H,
6.7%; N, 9.3%.
The starting material was prepared as follows:
i) To a solution of 4-chloroquinoline (3 g) in mixed xylenes (b.p.
137.degree.-144.degree. C.) (25 ml) was added 1 -benzylpiperazine (6.46
g). The mixture was heated to reflux with stirring for 20 hours then
cooled to room temperature. The precipitate that formed was filtered and
washed with xylene. To the combined filtrate and washings was added
decolourising charcoal and the mixture was heated to reflux for 20
minutes, cooled and filtered through kieselguhr. The filtrate was
evaporated to dryness to yield 1-benzyl-4-(4-quinolinyl)piperazine (4.55
g) as a yellow solid: m.p. 105.degree.-106.degree. C.; NMR (CDCl.sub.3)
.delta. 2.75(4H,m), 3.26(4H,m), 3.66(2H,s) 6.84(1H,d), 7.35(5H,m),
7.45(1H,m), 7.65(1H,m), 8.03(2H,m), 8.73(1H,m); m/Z 304 (M+H).sup.+.
ii) To a solution of the product of step i) (3 g) and p-toluene sulphonic
acid monohydrate (3.79 g) in methanol (300 ml) under argon was added 10%
Pd on C (1.5 g). The mixture was covered with a blanket of hydrogen and
stirred vigorously at room temperature for 24 hours. The catalyst was
filtered off through a pad of kieselguhr and the filtrate was evaporated
to dryness. The oily residue was partitioned between water, ethyl acetate
and a small volume of methanol, basified to pH9-10 by addition of 1N NaOH
(aq.) and the organic layer was separated. The aqueous layer was saturated
with salt and re-extracted a number of times with dichloromethane. The
organic extracts were dried (MgSO.sub.4) and evaporated to yield a 1:1
mixture of 1-(4-quinolinyl)piperazine and
1-(5,6,7,8-tetrahydroquinolin-4-yl)piperazine (1.84 g) as a yellow solid
which was used without further purification: m/Z 214 and 218 (M+H).sup.+
for two products.
EXAMPLE 46
4-2-4-(5,6,7,8-Tetrahydro-4-quinolinyl)piperazin-1-yl!acetyl!phenoxyaceti
c acid
In a similar manner to Example 42, the product of Example 45 (180 mg), and
0.5% v/v triethylamine/water (40 ml) gave, after stirring overnight at
room temperature, washing with ether, filtration and lyophilisation, the
title compound (121 mg) as an off-white fluffy solid: NMR (CDCl.sub.3)
.delta. 1.75(2H,m), 1.90(2H,m), 2.61(2H,m), 2.75(4H,m), 3.08(2H,m),
3.23(4H,m), 3.78(2H,s), 4.66(2H,s), 6.79(1H,d), 6.99(2H,d), 7.98(2H,d),
8.41(1H,d); m/Z 410 (M+H).sup.+ ; calculated for C.sub.23 H.sub.27 N.sub.3
O.sub.4. 0.03 Et.sub.3 N. 1.0 H.sub.2 O: C, 64.7%; H, 6.89%; N, 9.86%;
found: C, 64.4%; H, 6.6%; N, 9.5%.
EXAMPLE 47
Methyl 4-2-4-(4-pyrimidinyl)piperazin-1-yl!acetyl!phenoxyacetate
To a mixture of 4-(1-piperazinyl)pyriimidine (preparation described in DE
2316920) (1.57 g) and triethylamine (3.87 g) in acetonitrile (40 ml) at
room temperature was added dropwise over about 0.5 hour a solution of
methyl 4-bromoacetylphenoxyacetate (2.73 g) in acetonitrile (25 ml). On
completion of the addition the reaction mixture was stirred at room
temperature for 2 days. The precipitated solid was filtered off, washed
with acetonitrile and the combined filtrate and washings evaporated to
dryness. The resultant red oil was purified by flash chromatography, first
on silica by elution with 1-5% v/v methanol/dichloromethane, then on
neutral alumina by elutioni with 3% v/v methanol/dichloromethane, to yield
the title compound (0.92 g) as an off-white solid: NMR (CDCl.sub.3)
.delta. 2.69(4H,m), 3.72(4H,m), 3.80(2H,s), 3.82(3H,s), 4.71(2H,s),
6.49(1H,m), 6.94(2H,d), 8.01(2H,d), 8.20(1H,d), 8.60(1H,s); m/Z 371
(M+H).sup.+ ; calculated for Cl.sub.19 H.sub.22 N.sub.4 O.sub.4.0.4
H.sub.2 O: C 60.4%; H, 6.09%; N, 14.8%; found: C, 60.7%; H, 6.2%; N,
14.7%.
EXAMPLE 48
4-2-4-(4-Pyrimidinyl)piperazin-1-yl!acetyl!phenoxyacetic acid
In a similar manner to Example 42, the product of Example 47 (200 mg) and
1% v/v triethylamine/water (40 ml) gave, after stifling overnight at room
temperature, washing with ether, filtration and lyophilisation, the title
compound (152 mg) as an off-white solid: NMR (d.sub.6 DMSO) .delta.
3.14(4H,m), 3.93(4H,m), 4.61(2H,brni), 4.83(2H,s), 7.03(1lH,d),
7.09(2H,d), 7.96(2H,d), 8.3 1 (1H,d), 8.65(1H,s); m/Z 357 (M+H).sup.+ ;
calculated for C.sub.18 H.sub.20 N.sub.4 O.sub.4.0.34 H.sub.2 O: C, 59.6%;
H, 5.75%; N, 15.5%; found: C, 59.2%; H, 6.0%; N, 15.0%.
EXAMPLE 49
1-Benzyl-3-4-(4-pyridyl)piperazin-1-yl!-4-quinolon-7-yl!oxyacetic acid
trifluoroacetate salt
To a stirred suspension of sodium hydride (80 mg) in dry DMF (5 ml) under
argon at room temperature was added
1-benzyl-3-4-(4-pyridyl)piperazin-1-yl!-4-quinolon-7-ol (377 mg),
followed, after 1 hour, by tert.butyl bromoacetate (0.13 ml). After
stirriing for a further 2 hours at room temperature under argon an extra
aliquot of sodium hydride (40 mg) was added, followed, dropwise, by a
further quantity of tert.butyl bromoacetate (0.13 ml). The reaction
mixture was stirred at room temperature overnight then evaporated to
dryness. The residue was purified by preparative rp-hplc on a DYNAMAX
C-18, 60A 83-201-C! column using an acetonitrile/water mobile phase
system containing 0.1% trifluoroacetic acid, to give, after
lyophilisation, the de-esterified product as a gum, which, on trituration
with water gave the title compound (22 mg) as an off-white solid: NMR
(d.sub.6 DMSO) .delta. 3.30(4H,m), 4.00(4H,m), 4.83(2H,s), 5.61(2H,s),
7.00(2H,m), 7.38(7H,m), 7.96(1H,s), 8.25(1H,d), 8.38 2H,d); m/Z 471
(M+H).sup.+ ; calculated for C.sub.27 H.sub.26 N.sub.4 O.sub.4.1.0
CF.sub.3 CO2H. 2.0 H.sub.2 O: C, 56.1 %; H, 5.04%; N, 9.0%; found: C,
56.4%; H, 4.9%; N, 8.9%.
The starting material was prepared as follows:
i) To a solution of 1-ethoxycarbonylpiperazine (20 g) and triethylamine
(14.1 g) in dichloromethane (200 ml) at 0.degree. C. was added gradually
with stirring over 10-15 minutes, methyl bromoacetate (20.3 g). On
completion of the addition the reaction mixture was stirred at room
emperature for 2 hours, washed with water and brine, dried (MgSO.sub.4)
and evaporated to yield
1-ethoxycarbonyl-4-methoxycarbonylmethylpiperazinie (29.1 g) as a
colourless oil: NMR (CDCl.sub.3) .delta. 1.28(3H,t), 2.56(4H,m),
3.25(2H,s), 3.52(4H,m), 3.72(3H,s), 4.14(2H,q); m/Z 231 (M+H).sup.+.
ii) To a solution of the product of step i) (10 g) in dry DMF (80 ml) was
added dimethylformamide dimethyl acetal (DMFDMA) (30 ml) and the reaction
mixture was heated to reflux. After 2 days a further quantity of DMFDMA
(30 ml) was added and refluxing was continued for a further 2 days. The
reaction mixture was evaporated and the residue partitioned between
aqueous ammonium chloride solution and ethyl acetate. The organic layer
was separated, washed with brine, dried (MgSO.sub.4) and evaporated. The
residue was purified by flash chromatography on silica by elution with
ethyl acetate to yield
1-ethoxycarbonyl-4-(1-dimethylaimno-2-methoxycarbonylethen-2-yl)piperazine
(7 g) as an orange oil: NMR (CDCl.sub.3) .delta. 1.28(3H,t), 2.90(4H,m),
3.14(6H,s), 3.50(4H,m), 3.64(3H,s), 4.12(2H,q), 7.01(1H,s); m/Z 286
(M+H).sup.+.
iii) A mixture of the product of step ii) (6.3 g), m-anisidine (2.5 ml),
ethanol (65 ml) and concentrated hydrochloric acid (2.2 ml) was stirred at
room temperature for 2 hours then evaporated. The residue was basified by
careful addition of aqueous sodium carbonate solution. The mixture was
extracted with ethyl acetate and the organic extracts were washed with
brine, dried (MgSO.sub.4) and evaporated to dryness. The residue was
purified by flash chromatography on silica by elution with 70% v/v
ether/hexane to yield
1-ethoxycarbonyl-4-(1-(3-methoxyphenyl)amino-2-methoxycarbonylethen-2-yl)p
iperazine (5.15 g) as an off-white solid: m.p. 120.degree.-122.degree. C.;
NMR (CDCl.sub.3) .delta. 1.28(3H,t), 2.90(4H,m), 3.50(4H,m), 3.71(3H,s),
3.81(3H,s), 4.18(2H,q), 6.52(3H,m), 7.21 (1H,t), 7.39(1H,d), 7.80(1 H,d);
m/Z 364 (M+H).sup.+.
iv) A mixture of the product of step iii) (8.5 g) and DOWTHERM (55 ml) was
heated to 230.degree.-270.degree. C. for 1 hour. The dark coloured mixture
was cooled to room temperature before excess hexane was added. Removal of
the supernatant by decantation followed by washing gave a crude residue
(4.66 g) which was used without further purification.
The residue (4.66 g) was added to a stirred mixture of 55% sodium hydride
in mineral oil (0.67 g) and dry DMF under argon at room temperature. After
stirring for 75 minutes benzyl bromide (1.86 ml) was added and the
reaction mixture was stirred at room temperature overnight then evaporated
and the residue partitioned between water and ethyl acetate. The organic
layer was separated, washed with brine, dried (MgSO.sub.4) and evaporated
to yield an oily residue which was purified by flash chromatography on
silica by elution with ethyl acetate to give the higher Rf product,
1-benzyl-3-(1-ethoxycarbonylpiperazin-4-yl)-7-methoxy-4-quinolone (1.8 g)
as an off-white solid: m.p. 173.degree.-4.degree. C.; NMR (CDCl.sub.3)
.delta. 1.28(3H,t), 3.05(4H,m), 3.70(4H,m), 3.75(3H,s), 4.18(2H,q),
5.27(2H,s), 6.59(1H,d), 6.89(1H,dd), 7.10(3H,m), 7.30(3H,m), 8.41 (1H,d);
m/Z 422 (M+H).sup.+.
v) A mixture of the product of step iv) (1.8 g), ethanol (40 ml) and 20%
w/v aqueous potassium hydroxide solution (40 ml) was heated to reflux
overnight, cooled and evaporated to dryness. The residue was partitioned
between water and dichloromethane and the organic layer was separated,
washed with brine, dried (MgSO.sub.4) and evaporated to yield
1-benzyl-3-(piperazin-1-yl)-7-methoxy-4-quinolone (1.5 g) as a yellow
foam: NMR (CDCl.sub.3) .delta. 2.80(1H,m), 3.20(8H,m), 3.73(3H,s),
5.28(2H,s), 6.59(1H,d), 6.88(1H,dd), 7.15(3H,m), 7.30(3H,m), 8.41(1H,d);
m/Z 350 (M+H).sup.+.
vi) A mixture of the product of step v) (1.1 g), xylene (110 ml), isoamyl
alcohol (11 ml), 4-chloropyridine hydrochloride (1.1 g) and triethylamine
(11 ml) was heated to reflux and stirred for 30 hours. During this period
extra aliquots of 4-chloropyridine hydrochloride (6.times.1.1 g) and
triethylamine (3.times.11 ml) were added at intervals. The reaction
mixture was evaporated to dryness and the residue was purified by flash
chromatography on silica by elution with
methanol/dichloromethanie/concentrated ammonia (20:200:1) to give
1-benzyl-3-(4-(4-pyridyl)piperazin-1-yl)-7-methoxy-4-quinolonc (780 mg) as
an orange-red solid: NMR (d.sub.6 DMSO) .delta. 3.2(4H,m), 3.75(3H,s),
3.80(4H,m), 5.55(2H,s), 6.90(2H,m), 7.30(7H,m), 7.88(1H,s), 8.13(1H,d),
8.24(2H,d); m/Z 427 (M+H).sup.+.
vii) To a solution of the product of step vi) (815 mg) in dry
dichloromethane (10 ml) under argon was added a 1M solution of boron
tribromide in dichloromethane (10 ml). The reaction was stirred at room
temperature for 14 days, extra aliquots of BBr.sub.3 solution being added
after 3 and 7 days. After 2 weeks, excess 1M aqueous sodium hydroxide
solution was added, dropwise at first, and the mixture stirred at room
temperature for 3 hours. The precipitated material was filtered off and
the aqueous layer of the filtrate separated. The pH of the aqueous layer
was adjusted to 8 by addition of 2N HCl (aq.) and 1M NaHCO.sub.3 (aq.)
before being extracted with ethyl acetate. The organic extracts were
washed with brine, dried (MgSO.sub.4) and evaporated to dryness to yield
1-benzyl-3-(4-(4-pyridyl)piperazil!-1-yl)-4-quinolon-7-ol (75 mg) as an
off-white solid: m.p. 141.degree.-6.degree. C.; NMR (d.sub.6 DMSO) .delta.
3.10(4H1,m), 3.50(4H,m), 5.40(2H,s), 6.67(1H,d), 6.72(1H,dd), 6.90(2H,m),
7.30(5H,m), 7.76(1H,s), 8.07(1H,d), 8.15(2H,s), 10.15(1 H,brs); m/Z 413
(M+H).sup.+.
EXAMPLE 50
Ethyl 4-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyrate
A stirred suspension of 4-(4-(4-pyridyl)piperazin-1 -yl)-phenol (1.34 g) in
dry DMF (20 ml) was treated with sodium hydride (60% dispersion in mineral
oil, 0.21 g) and the mixture stirred for 1 hour. To the resulting solution
was added ethyl 4-bromobutyrate and the mixture was stirred for 16 hours.
Solvent was evaporated under reduced pressure and the residue was
partitioned between ethyl acetate and water. The organic layer was washed
with water, filtered through phase separating paper (Whatman 1PS) and
evaporated. The residue was purified by flash chromatography on silica,
eluting with 1.5/92.5/6 v/v/v methanol/ethyl acetate/aqueous ammonia (SG
0.89) and recrystallised firom ethyl acetate/hexane to give the title
compound (0.7 g) as a solid: m.p. 84.degree.-85.degree. C.; NMR
(CDCl.sub.3) .delta. 8.3(2H,d); 6.86(4H,c) 6.72(2H,d); 4.12(2H,q);
4.0(2H,t); 3.47(4H,m); 3.20(4H,m); 2.5(2H,t); 2.1(2H,m); 1.26(3H,t); m/e
370(M+H).sup.+ ; calculated for C.sub.21 H.sub.27 N.sub.3 O.sub.3 C, 68.3;
H, 7.4; N, 11.4. Found: C, 68.1; H, 7.4; N, 11.1%.
The starting material was prepared as follows:
i) 4-(Piperazin-1-yl)anisole (4.24 g) and 4-chloropyridine hydrochloride
(3.35 g) were intimately mixed and heated at 160.degree.-170.degree. C.
(bath temperature) for 7 minutes. The solid obtained on cooling was
dissolved in water (75 ml) and the solution basified with aqueous ammonia.
The solid precipitate was extracted into ethyl acetate and the organic
extract washed with water, filtered through phase separating paper
(Whatman 1PS) and evaporated. The residue was recrystallised from ethanol
to give 4-4-(4-pyridyl)piperazin-1-yl!anisole (1.84 g) as a solid: m.p.
165.degree.-167.degree. C.; NMR (CDCl.sub.3) .delta. 8.3(2H,d);
6.86(4H,m); 6.71(2H,d); 3.78(3H,s); 3.46(4H,m); 3.2(4H,m).
ii) The product from step i) (1.5 g) in concentrated hydrobromic acid (30
ml) was heated under argon at 130.degree.-135.degree. C. for 2 1/2 hours.
The solution was cooled, poured into water (150 ml) and basified with
aqueous ammonia. The precipitate was filtered, washed with water and dried
to give 4-4-(4-pyridyl)piperazin-1-yl!phenol (1.36 g) as a solid: m.p.
310.degree.-312.degree. C.; NMR (d.sub.6 DMSO) .delta. 8.2(2H,d);
6.8(4H,m); 6.66(2H,d); 3.45(4H,m); 3.08(4H,m).
EXAMPLE 51
4-4-4-(4-Pyridyl)piperazin-1-yl!phenoxy!butyric acid
A solution of the product of Example 50 (0.1 g) in aqueous sodium hydroxide
(1N, 0.8 ml) and ethanol (2 ml) was kept for 2 hours. The solution was
evaporated and the residue dissolved in water (5 ml). Hydrochloric acid
(1N, 0.8 ml) was added and the precipitate was filtered and washed with
water and ether to give the title compound as a solid: m.p.
305.degree.-306.degree. C.; m/e 342 (M+H).sup.+ ; NMR (d.sub.6 DMSO)
.delta. 8.0(2H,d), 6.72(6H1,m); 3.74(2H,t); 3.3(4H,m); 2.94(4H,m);
2.19(2H,t); 1.72(2H,m); calculated for C.sub.19 H.sub.23 N.sub.3 O.sub.3 :
C, 66.8; H, 6.8; N, 12.3. Found: C, 67.0; H, 6.8; N, 12.2%.
EXAMPLE 52
Ethyl 5-4-4-4-pyridyl)piperazin-1-yl!phenoxy!pentanoate
In a similar manner to Example 50, but starting from ethyl
5-bromopentanoate, was prepared the title compound in 41% yield (from
ethyl acetate/hexane): m.p. 79.degree.-82.degree. C.; NMR (CDCl.sub.3)
.delta. 8.2(2H,d), 6.88(4H,m), 6.7(2H,d), 4.13(2H,q), 3.47(4H,m),
3.17(4H,m), 2.36(2H,m), 1.8(4H,m), 1.33(3H,t); m/e 384(M+H).sup.+,
calculated for C.sub.22 H.sub.29 N.sub.3 O.sub.3.0.25H.sub.2 O: C, 68.1;
H, 7.6; N, 10.8. Found: C, 68.2; H, 7.8; N, 10.5%.
EXAMPLE 53
5-4-4-(4-Pyridyl)piperazin-1-yl!phenoxy!pentanoic acid
In a similar manner to Example 51, but starting from the product of Example
52, the title compound was made in 50% yield: m.p. 237.degree.-241.degree.
C.; NMR (d.sub.6 DMSO) .delta. 8.2(2H,d); 6.97(4H,m), 6.83(2H,d);
3.69(2H,t), 3.57(4H,m), 3.13(4H,m); 2.27(2H,t), 1.67(4H1,m); m/e
356(M+H).sup.+ ; calculated for C.sub.20 H.sub.25 N.sub.3 O.sub.3
0.75H.sub.2 O: C, 65.0; H, 7.2; N, 11.3. Found: C, 65.0; H, 6.9; N, 11.1%.
EXAMPLE 54
Ethyl 4-4-(4-pyridyl)piperazin-1-yl!phenoxycrotonate
In a similar manner to Example 50, but starting from ethyl
4-bromocrotoniate, was prepared the title compound in 3% yield (from ethyl
acetate/hexanie): m.p. 127.degree.-128.degree. C.; NMR (CDCl.sub.3)
.delta. 8.3(2H,d), 7.1(1H,m), 6.9(4H,m), 6.7(2H,m), 6.18(2H,m),
4.66(2H,m), 4.25(2H,q), 3.49(4H,m), 3.2(4H,m), 1.3(3H,t); m/e
368(M+H).sup.+ ; calculated for C.sub.21 H.sub.25 N.sub.3 O.sub.3 : C,
68.6; H, 6.9; N, 11.4. Found C, 68.4; H, 6.9; N, 10.7%.
EXAMPLE 55
3-3-4-(4-Pyridyl)piperazin-1-ylmethyl!!benzamido-3-phenylpropionic acid
Sodium hydroxide solution (1N, 0.5 ml) was added to a solution of methyl
3-3-4-(4-pyridyl)piperazin-1-ylmethyl!!benzamido-3-phenylpropionate
(0.116 g) in methanol (5 ml) at room temperature. After 16 hours,
hydrochloric acid (1N, 0.5 ml) was added and the solution evaporated to
dryness. The residue was warmed with dichloromethane (5 ml) and the
insoluble solid was isolated by decantation and heated in water (5 ml) to
give, after cooling a solid (0.062 g); NMR (d.sub.6 DMSO/CD.sub.3 COOD)
.delta. 8.13(2H,d), 7.77(2H,m), 7.14-7.5(7H, complex), 7.06(2H,d),
5.42(1H,m), 3.56(6H,d), 2.8(2H,m); inme 445(M+H).sup.+ : calculated for
C.sub.26 H.sub.28 N.sub.4 O.sub.3. 0.5H.sub.2 O: C,68.9; H, 6.44; N,
12.35. Found: C, 68.7; H. 6.5; N, 12.2%.
The starting material was prepared as follows:
i) A solution of 3-chloromethyl benzoyl chloride (0.189 g) in DMF (2 ml)
was added to a mixture of methyl 3-amino-3-phenylpropionate hydrochloride
(0.215 g) and triethylamine (0.35 ml) in DMF (15 ml) with stirring at room
temperature. After 3 hours, water (50 ml) was added and the mixture was
extracted with dichloromethane. The organic layer was dried (MgSO.sub.4)
and evaporated to give an oil which solidified under high vacuum to give
methyl 3-(3-chloromethyl)benzamido-3-phenylpropionate in 100% yield; NMR
(CDCl.sub.3) .delta. 7.72-8.7(10H, complex), 5.62(1H,m), 4.6(2H,s),
3.66(3H,s), 3.0(2H,m).
ii) A solution of 1-(4-pyridyl)piperazine (0.33 g) in acetonitrile (7.5 ml)
was added to a stirred solution of the product of step i) in acetonitrile
(5 ml). After sixteen hours at room temperature, the mixture was filtered
and the filtrate evaporated. The residue was dissolved in dichloromethane
(75 ml) and the solution washed with water (2.times.25m1), dried
(MgSO.sub.4) and evaporated. The residue was purified by flash column
chromatography, the product being eluted with 5% v:v methanol in
dichloromethane to give methyl
3-3-4-(4-pyridyl)piperazin-1-ylmethyl!!benzamido-3-phenylpropionate as a
solid (0.18 g); NMR (CDCl.sub.3) .delta. 8.35(2H,d); 7.85(1H,s),
7.72(1H,m), 7.39(7H,m), 6.68(2H,d), 5.62(1H,m), 3.65(3H,s), 3.6(2H,s),
3.0(2H,m); m/e 459 (M+H).sup.+ ; calculated for C.sub.27 H.sub.38 N.sub.4
O.sub.3.0.5H.sub.2 O: C, 69.3; H,6.6; N,12. Found: C, 69.1; H, 6.6; N,
11.8%.
EXAMPLE 56
Methyl 3-4-4-(4-pyridyl)piperazin-1-yl!!benzaminopropionate
Methyl 3-aminopropionate hydrochloride (0.195 g) and triethylamine (0.59
ml) were added to a stirred suspension of
4-(4-pynidyl)piperazini-1-yl!benzoyl chloride hydrochloride (0.473 g) at
room temperature. The mixture was stirred for two days and solvent removed
under reduced pressure. The residue was purified by flash column
chromatography. The product was obtained by elution with 1/9/0.1 v:v:v
methanol/dichloromethane/0.88 S.G. aqueous ammonia as a solid which was
recrystallised from ethyl acetate to give the title compound (0.2 g): m.p.
197.degree.-199.degree. C.; NMR (d.sub.6 DMSO) .delta. 8.19(2H,d);
7.72(2H,d); 7.13(2H,d); 6.90(2H,d); 3.82(4H,m); 3.56(3H,s); 3.48(6H,m),
2.50(2H,t); m/e 369(M+H).sup.+ ; calculated for C.sub.20 H.sub.24 N.sub.4
O.sub.3.0.25H.sub.2 O: C,64.4; H, 6.6; N, 15.0. Found: C,64.3; H, 6.6; N,
14.9%.
The starting material was prepared as follows:
i) An intimate mixture of 1-(4-pyridyl)piperazine (1.63 g) and
4-bromobenzoic acid (1.05 g) was heated at 220.degree. C. for 6 hours. The
resulting glass was cooled and triturated with methanol (50 ml) to give,
as an off-white solid, 4-((4-pyridyl)piperazin-1-yl)benzoic acid;
m.p>350.degree. C.; IR(cm.sup.-1) 1682, 1600, 1514, 1236, 1013.
(ii) Oxalyl chloride (0.5 ml) was added to a stirred suspension of
4-((4-pyridyl)piperazin-1-yl)benzoic acid in dichloromethane (15 ml),
followed by DMF (1 drop). The mixture was stirred for 2 hours and
evaporated to dryness to give 4-(4-pyridyl)piperazin-1-yl!benzoyl
chloride which was used immediately.
EXAMPLE 57
3-4-4-(4-Pyridyl)piperazin-1-yl!!benzamidopropionic acid
To a solution of the product of Example 56 (0.062 g) in methanol (1 ml) was
added sodium hydroxide solution (1N, 0.1 7 ml) and the solution kept for 4
days at room temperature. Hydrochloric acid (1N, 0.17 ml) was added to
give the title compound as a solid (0.052 g); m.p. >330.degree. C.; NMR
(d.sub.6 DMSO) 6.96(2H,d); 3.76(4H,m); 3.46(6H, complex); 2.5(2H,m); m/e
355 (M+H).sup.+ ; calculated for C.sub.19 H.sub.22 N.sub.4 O.sub.3.0.7
H.sub.2 O: C, 62.2; H, 6.4; N, 15.3. Found: C, 62.3; H, 6.4; N, 15.3%.
EXAMPLE 58
Methyl 3-4-4-(4-pyridyl)piperazin-1-yl!benzamido!-3-phenylpropionate
In a similar manner to Example 56, but starting from methyl
3-amino-3-phenylpropionate, was prepared the title compound in 26% yield
as a solid (after trituration with hot ethyl acetate); NMR (d.sub.6 DMSO)
.delta. 8.6(1H,d); 8.2(1H,brs); 7.75(2H,d); 7.3(5H,m); 7.0(2H,d); 6.85(2H,
brs); 5.45(1H,m); 3.55(3H,s); 3.45(8H,m), 292(2H,m); m/e 355
445(M+H).sup.+ ; calculated for C.sub.26 H.sub.28 N.sub.4 O.sub.3.
0.5H.sub.2 O: C, 68.9; H, 6.4; N, 12.4. Found. C, 68.7; H, 6.3; N, 12.3%.
EXAMPLE 59
3-4-4-(4-Pyridy)piperazin-1-yl!benzamido!-3-phenylpropionic acid
In a similar manner to Example 51, but starting from the product of Example
58, was prepared the title compound in 73% yield as a solid; NMR (d.sub.6
DMSO) .delta. 8.61(1H,d); 8.2(2H,brs); 7.78(2H,d); 7.3(5H,m); 7.0(2H,d);
6.9(2H,d); 5.43(1H,m); 3.45(8H,m); 2.82(1 H,m); m/e 431 (M+H).sup.+ ;
calculated for C.sub.25 H.sub.26 N.sub.4 O.sub.3 0.5H.sub.2 O: C, 68.3; H,
5.9; N, 12.8 Found: C, 68.3; H, 6.0; N, 12.9%.
EXAMPLE 60
Methyl 3-4-4-(4-pyridyl)piperazin-1-yl!benzamido!butyrate
In a similar manner to Example 56, but starting from methyl
3-aminobutyrate, was prepared the title compound in 11% yield
(recrystallised from ethyl acetate/hexane) as a solid; m.p.
130.degree.-132.degree. C.; NMR (d.sub.6 DMSO) .delta. 8.28(2H,d);
8.07(1H,d); 7.77(2H,d); 7.13(2H, 7.0(2H,d); 4.36(1H,m); 3.74(4H,m);
3.6(3H,s); 3.48(4H,m); 2.55(2H,m); 1.2(3H,d); m/e 383(M+H).sup.+ ;
calculated for C.sub.21 H.sub.26 N.sub.4 O.sub.3.0.25H.sub.2 O: C, 65.2;
H, 6.9; N, 14.5. Found: C, 65.3; H, 6.8; N, 14.4%.
EXAMPLE 61
Methyl 4-2-4-(4-pyridyl)piperazin-2-one-1-yl!acetyl!phenoxyacetate
A dispersion of potassium hydride in mineral oil (35% w/w, 0.63 g) was
added to a stirred suspension of 4-(4-pyridyl)piperazin-2-one (0.885 g) in
DMF (10 ml) and the mixture was stirr-ed at room temperature for 2 hours.
To the anion thus formed, was added methyl 4-bromoacetylphenoxyacetate
(1.44 g) and the mixture was stirred at room temperature for 20 hours.
Solvent was evaporated and the residue partitioned between dichloromethane
(20 ml) and water (20 ml). The organic layer was dried (MgSO.sub.4) and
evaporated. The residue was purified by flash column chromatography, the
product being eluted with 1/9/0.1 v:v:v methanol/dichloromethane/0.88 S.G
aqueous ammonia. Recrystallisation from ethyl acetate gave the title
compound, m.p. 164.degree.-165.degree. C.; NMR (d.sub.6 DMSO) .delta.
8.2(2H,d), 7.97(2H,d), 7.08(2H,d), 6.83(2H,d), 4.93(4H,d), 4.02(2H,s),
3.71(3H,s), 3.7(2H,m), 3.52(2H,m); m/e 384 (M+H).sup.+ ; calculated for
C.sub.20 H.sub.21 N.sub.3 O.sub.5 : C, 62.7; H, 5.52; N, 11.0. Found: C,
62.6; H, 5.6; N, 10.9%.
The starting material was prepared as follows:
i) An intimate mixture of piperazinone (4.2 g) and 4-chloropyridine
hydrochloride (7.33 g) was stirred and heated at 200.degree. C. for 10
minutes and allowed to cool. The product was purified by flash column
chromatography and cluted with 1/9/0.1 v:v:v methanol/methylene
chloride/0.88 S.G. aqueous ammonia. The solid thus obtained was
recrystallised from ethanol to give 4-(4-pyridyl)piperazin-2-one (1.75 g);
m.p. 268.degree.-270.degree. C.; NMR (d.sub.6 DMSO) .delta. 8.2(3H,m);
6.8(12H,m); 3.85(2H,s); 3.52(2H,m); 3.31(2H,m); m/e 178(M+H).sup.+.
EXAMPLE 62
4-2-4-(4-Pyridyl)piperazin-2-one-1-yl!acetyl!phenoxyacetic acid
In a similar manner to Example 51, but starting from the product of Example
61, was prepared the title compound in 20% yield as a solid NMR (d.sub.6
DMSO) .delta. 8.22(2H,d), 7.97(2H,d), 7.04(2H,d), 6.89(2H,d); 4.93(2H,s),
4.77(2H,s), 4.07(2H,s), 3.72(2H,m), 3.49(2H,m); m/e 370(M+H).sup.+ ;
calculated for C.sub.19 H.sub.19 N.sub.3 O.sub.5. 2.5H.sub.2 O: C, 55.1;
H, 5.8; N, 10.1. Found: C, 55.1; H, 5.3; N, 10.6%.
EXAMPLE 63
Methyl 4-4-(4-pyridyl)piperazin-1-yl!carboxamido!phenoxy acetate
To a solution of 1-(4-pyridyl)piperazine (0.4 g) in dichlorornethane (10
ml) was added a solution of methyl 4-isocyanatophenoxyacetate (0.5 g) in
dichloromethane (5 ml). The resulting solution was stirred for 3 hours at
room temperature. Solvent was evaporated and the residue triturated with
ethanol to give the title compound as a solid (0.155 g); NMR (d.sub.6
DMSO) .delta. 8.55(1H,s), 8.22(2H,d), 7.28(2H,d), 7.02(2H,d), 6.82(2H,d),
4.72(2H,s), 3.7(3H,s), 3.58(8H,m); n/e 371(M+H).sup.+ ; calculated for
C.sub.19 H.sub.22 N.sub.4 O.sub.4.H.sub.2 O: C, 58.8; H, 6.2; N, 14.4
Found: C, 58.7; H, 5.8; N, 14.8%.
The starting material was prepared as follows:
Methyl 4-aminophenoxyacetate (2.2 g) in ethyl acetate (dried with calcium
chloride) (50 ml) was added dropwise to a stirred solution of phosgene in
toluene (115 ml, .about.2M) at 75.degree. C. After addition the mixture
was stirred at 75.degree. C. for 1.5 hours and at 95.degree.-105.degree.
C. for 16 hours. Solvent was evaporated to give an oil (2.5 g); IR shows a
strong band at 2273 cm.sup.-1.
EXAMPLE 64
4-4-(4-Pyridyl)piperazin-1-yl!carboxamido!phenoxyacetic acid
In a similar manner to Example 51, but starting from the product of Example
63, was prepared the title compound in 86% yield as a solid; NMR (d.sub.6
DMSO) .delta. 8.45(11H,s); 8.2(2H,d), 7.35(2H,d), 6.35(4H,m), 4.55(2H,s),
3.49(8H,m), m/e 357(M+H).sup.+ ; calculated for C.sub.18 H.sub.20 N.sub.4
O.sub.4.0.75 H.sub.2 O: C, 58.5; H, 5.8; N, 15.2. Found: C, 58.5; H, 5.9;
N, 15.1%.
EXAMPLE 65
Ethyl-4-4-(4-pyridyl)piperazin-1-yl!-4-quinolon-3-ylcarboxylic acid
A mixture of 1-ethyl-7-chloro-4-quinolon-3-ylcarboxylic acid (182 mg) and
1-(4-pyridyl) piperazine (125 mg ) was heated to 200.degree. C. for 20
minutes. The mixture was cooled and methanol (5 ml) was added. The
resulting solid was filtered and washed with methanol (10 ml) to give the
title compound (68 mg), as a solid: NMR (d.sub.6 DMSO) .delta. 1.4(t,3H),
3.75-3.85(m,4H), 3.9-4.0(m,4H), 4.55(q,2H), 6.9(d, 1 H), 7.2(d,2H),
7.3(dd, 1H), 8.2(d, 1H), 8.3(d,2H), 8.9(s, 1H); m/e 379(M+H).sup.+
EXAMPLE 66
Methyl
2-RS-(n-butylsulphonylamino)-3-4-2-4-(4-pyridyl)piperazin-1-yl!acetyl!p
henyl!propionate
To a solution of 1-(4-pyridyl) piperazine (296 mg) and triethylamine (0.25
ml) in acetonitrile (10 ml) was added, dropwise, over 30 minutes a
solution of methyl-2-RS-(n-butylsulphonylamino)-3-(4-bromoacetylphenyl)
propionate (382 mg) in acetonitrile (8 ml). The mixture was stirred for an
additional 4 hours. The solvent was removed by evaporation to give an oil
which was purified by flash column chromatography on silica, eluting with
methanol/dichloromethane (5:95 to 10:90 v/v) to give the title compound as
a solid (202 mg): NMR (d.sub.6 DMSO) 0.7(t,3H), 1.05-1.4(m,4H),
2.55-2.7(m,4H), 2.8-3.2(m,4H), 3.25-3.4(m,4H), 3.65(s,3H), 3.9(s,2H),
4.1-4.25(m, 1H), 6.85(d,2H), 7.45(d,2H), 7.95(d, 1H), 7.95(d,2H),
8.15(d,2H); m/e 503(M+H).sup.+ ; calculated for C.sub.25 H.sub.34 N.sub.4
O.sub.5 S.0.5H.sub.2 O: C, 58.7; H, 6.85; N, 10.9. Found: C, 58.8; H, 6.9;
N, 10.6.
The starting material was prepared as follows:
i) Methyl 2-amino-3-(4-acetylphenyl)propionate was prepared by the method
described by M.P. Doyle JOC (1977), 42, 2431 and G,H.Cleland JOC (1969),
34, 744.
ii) n-Butylsulphonyl chloride(0.6ml) was added dropwise over 15 minutes to
a solution of the product of step i) (926 mg) and triethylaminc (0.7 ml)
in dichloromethane (20 ml). The resulting mixture was stirred for a
further 3 hours before it was poured into water (10 ml) and extracted with
dichloromethane (3.times.20 ml). The organic extracts were combined, dried
(MgSO.sub.4) and then evaporated to give a gum. Purification by flash
column chromatography on silica, eluting with ethyl acetate/hexane (40:60
v/v) gave methyl 2-RS-(n-butylsulphonylamino)-3-(4-acetylphenyl)propionate
(794 mg) as a solid: NMR (d.sub.6 DMSO) 6 0.75(t,3H), 1.0-1.4(m,4H),
2.55(s,3H), 2.65(s,3H), 2.8-2.95(m,2H), 3.05-3.2(m,2H), 3.65(s,3H),
4.1-4.25(m,1H), 7.45(d,2H), 7.85(d,1H), 7.9(d,2H); m/e 342(M+H).sup.+.
iii) To a suspension of CuBr.sub.2 (822 mg) in ethyl acetate (8 ml) at
reflux was added, dropwise over 10 minutes, a solution of the product from
step ii) in chloroform (8 ml). The resulting mixture was refluxed for 3
hours. The imxture was cooled, filtered and the solvent was removed by
evaporation to give an oil. Purification by flash column chromatography on
silica, eluting with ethyl acetate/hexane (10:90 to 50:50 in 10%
increments v/v) gave methyl
2-RS-(n-butylsulphonylano)-3-(4-bromoacetylphenyl) propionate (387 mg) as
an oil: NMR (CDCl.sub.3) .delta. 0.9(t,3H), 1.25-1.4(m,2H), 1.6-1
75(m,2H), 2.75-2.85(m,2H), 3.05-3.3(m,2H), 3.8(s,3H), 4.35-4.45(m, 1H),
4.4(s,2H), 4.8(d,1H), 7.35(d,2H), 7.95(d,2H); nme 420/422 (M+H).sup.+, Br
pattern.
EXAMPLE 67
2-RS-(n-Butylsulphonylamino)-3-4-2-4-(4-pyridyl)piperazine-1-yl!acetyl!p
henyl!propionic acid
To a solution of the product of Example 66 (105 mg) in methanol (4mi) was
added 2N sodium hydroxide (0.25 ml) and the resulting solution was stirred
for 3 hour. The mixture was concentrated, dissolved in water (2 ml) and
acidified with acetic acid. The resulting solution was transferred to a
reverse phase hplc column (Dynamax C18 83-201-C 60A) and eluted with 0.1%
TFA in water/acetonitrile. The pure fractions, on freeze drying, gave the
title compound (89 mg) as a solid: NMR (d.sub.6 DMSO) .delta. 0.8(t,3H),
1.15-1.6(m,4H), 2.75(t,2H), 2.9-3.05(m, 1H), 3.2-3.3(m, 1H),
3.4-3.5(m,4H), 3.95-4.2(m,5H), 4.95(s,2H), 7.25(d,2H), 7.55(d,2H),
8.0(d,2H), 8.35(d,2H); m/e 489(M+H).sup.+ ; calculated for C.sub.24
H.sub.32 N.sub.4 O.sub.5 S.3 CF.sub.3 COOH: C, 43.4 ; H, 4.2 ; N, 6.7 ;
TFA, 41.2. Found C, 43.7 ; H, 4.3; N, 6.8; TFA, 42.7.
EXAMPLE 68
2-RS-(n-Butylsulphonylamino)-3-4-(4-pyridyl)piperazin-1-yl
methylene!phenylpropionic acid
To a solution of ethyl 2-RS-(n-butylsulphonylamino)-3-
4-(4-pyl-idyl)piperazin-1-yl methylene!phenylpropionatc in methanol (3
ml) was added 2N sodium hydroxide (0.3 ml). The mixture was stirred for 3
hours and then concentrated. The resulting slurry was dissolved in water
(2 ml) and acidified with acetic acid. The resulting solution was
transfered to a reverse phase hplc column (Dynamax C18 83-201-C 60 A) and
eluted with 0.1% TFA in water/acetonitric. The pure product fractions, on
freeze drying, gave the title compound (165 mg) as a solid: NMR (d.sub.6
DMSO) 6 0.8(t,3H), 1.1-1.6(m,4H), 2.65-2.95(m,4H), 3.2-3.3(m,4H),
3.85-4.0(mn,4H), 4.05-4.15(m,1H), 4.3(s,2H), 7.2(d,2H),
7.4s,5H),8.3(d,62H); m/e 461(M+H).sup.+ ; calculated for C.sub.23 H.sub.32
N.sub.4 O.sub.4 S.H.sub.2 O, 2CF.sub.3 COOH: C, 45.9; H, 5.1; N, 7.9.
Found C, 45.5 ; H, 4.8 ; N, 7.5.
The starting material was prepared as follows:
i) To a solution of .alpha.,.alpha.'-dibromo-p-xylene (6.59 g),
N-(diphenylmethylene) glycine ethyl ester (4.76 g) and potassium iodide in
1,4-dioxane (120 ml), cooled to 10.degree. C., was added 40% aq.
benzyltrimethylammonium hydroxide(7.45 ml) over 1 hour. The mixture was
allowed to warm to room temperature and then to stir for 2.5 hours. The
mixture was partitioned between water (50 ml) and ethyl acetate (100 ml).
The organic layer was separated, dried (MgSO.sub.4) and evaporated to give
an oil. Purification by flash column chromatography on silica, eluting
with etheilhexane (10:90 v/v) gave ethyl RS-N-(diphenylmethylene)-4-
(bromomethyl)phenylalanine ethyl ester (3.58 g) as an oil: NMR (d.sub.6
DMSO) .delta. 1.5(t,3H), 3.0-3.2(m,2H), 4.05-4.15(m,3H), 4.65(s,2H),
6.55-6.65(m,2H), 7.0(d,2H),7.25(d,2H), 7.3-7.5(m,8H); n/e
450/452(M+H).sup.+ Br pattern.
ii) To a warm solution of 1-(4-pyridyl)piperazine (296 mg) and
triethylamine (0.14 ml) in acetonitrile (1 ml) was added slowly over 40
minutes a solution of the product from step i) (409 mg) in acetonitrile (5
ml). The resulting mixture was stirred at room temperature for 18 hours.
The mixture was concentrated and purified by flash column chromatography
on silica, eluting with methanol/dichloromethane (3:97 to 10:90 v/v) to
give
RS-N-(diphenylmethylene)-4-4-(4-pyridyl)piperazin-1-ylmethylene!phenyl-al
anine ethyl ester (305 mg) as a solid: NMR (d.sub.6 DMSO) .delta.
1.15(t,3H), 2.4-2.5(m,4H), 3.0-3.2(m,2H), 3.25-3.35(m,4H), 3.45(s,2H),
4.05-4.15(m,3H), 6.65(d,2H), 6.75(d,2H), 7.0(d,2H), 7.15(d,2H),
7.35-7.5(m,8H), 8.1(d,2H); m/e 533(M+H).sup.+.
iii) To a suspension of the product from step ii) in ether (5 ml) was added
1N hydrochloric acid (2.2 ml) and the resulting mixture was stirred for 1
hour. The mixture was partitioned between ether (20 ml) and 1N
hydrochloric acid (10 ml). The acid layer was separated, basified with
aqueous sodium bicarbonate and extracted with dichloromethane (3.times.20
ml). The organic extracts were combined, dried (MgSO.sub.4) and evaporated
to give RS-4-4-(4-pyridyl)-piperazin-1-ylmethylene!phenytalanine ethyl
ester as an oil: NMR (d.sub.6 DMSO) .delta. 1.1 (t,3H), 2.4-2.5(m,4H),
2.7-2.9(m,2H), 3.2-3.35(m,4H), 3.5-3.6(m,1H), 4.0(q,2H), 6.8(m,2H),
7.2(dd,4H), 8. I(bm,2H); m/e 369(M+H).sup.+.
iv) To a solution of the product of step iii) (1 37 mg) and triethylamine
(0.11 ml) in tetrahydrofuran (5 ml) was added 0.75 ml of a stock solution
of n-butylsulphonyl chloride 0.2 ml in 3 ml of tetrahydrofuran) and the
resulting mixture was stirred for 3 hours. The solvent was removed by
evaporation to give a gum. Purification by flash column chromatography on
silica, eluting with methanol/dichloromethane (5:95 to 10:90 v/v) gave
ethyl
2-(RS)-(n-butylsulphonylamino)-3-4-(4-pyridyl)piperazin-1-ylmethylenelphe
nylpropionate as a solid which was used without further purification.
EXAMPLE 69
Methyl 3-6-4-(4-pyridyl)piperazin-1-yl!pyrid-3-ylcarboxamido!propionate
To 6-4-(4-pyridyl)piperazin-1-yl!nicotiniic acid was added
dimethylformamide (0.1 ml) and thionyl chloride (5 ml)and the resulting
mixture was refluxed for 2 hour. The excess thionyl chloride was removed
by evaporation and the resulting solid was suspended in dichloromethane
(10 ml) to which was added methyl-3-aminopropionate hydrochloride (546
mg). The resulting mixture was cooled to 5.degree. C. and triethylamine(3
ml) was added dropwise over 15 minutes. The mixture was stirred at room
temperature for 18 hours. The mixture was partitioned between
dichloromethane(50 ml) and aqueous sodium bicarbonate(25 ml). The organic
layer was separated, dried (MgSO.sub.4), and evaporated to give a gum.
Purification by flash column chromatography on silica, eluting with
methanol/dichloromethane (6:94 to 15:85 v/v), gave the title compound (339
mg) as a gum: NMR (d.sub.6 DMSO) .delta. 2.6(t,2H), 3.4-3.5(m,2H),
3.5-3.6(m,4H), 3.6(s,3H), 3.7-3.8(m,4H), 6.9-7.0(m,3H), 8.0(dd,1H),
8.2(d,2H), 8.35(t,1H), 8.6(d,1H); m/e 370(M+H).sup.+ ; calculated for
C.sub.19 H.sub.23 N.sub.5 O.sub.3.1.5H.sub.2 O: C, 57.6; H, 6.5; N, 17.6.
Found: C, 57.3; H,5.9; N,17.5.
The starting material was prepared as follows:
i) A mixture of 6-chloronicotinic acid (3.21 g) and 1-(4-pyridyl)
piperazine (3.32 g) was heated to 220.degree. C. for 3 minutes. The
mixture was cooled and methanol (10 ml)was added. The resulting suspension
was boiled for 10 minutes, cooled and filtered to give
6-4-(4-pyridyl)piperazin-1-yljnicotinic acid (2.51 g) which was used
without further purification.
EXAMPLE 70
3-6-4-(4-Pyridyl)piperazin-1-yl!pyrid-3-ylcarboxamido!propionic acid
To a solution of the product of Example 69 (136 mg) in methanol (8 ml) was
added 2N sodium hydroxide (0.9 ml). The mixture was stirred for 3h and
then concentrated. The resulting gum was dissolved in water (4 ml) and
acidified with acetic acid. The precipitate was filtered and washed with
water to give the title compound (83 mg) as a solid: NMR (d.sub.6
DMSO+TFA) .delta. 2.5-2.6(m,2H), 3.45-3.55(m,2H), 3.95-4.1 l(m,8H),
7.2(d,2H), 7.4(d,1H), 8.3-8.4(m,3H), 8.55(d,1H); m/e 356(M+H).sup.+ ;
calculated for C.sub.18 H.sub.21 N.sub.5 O.sub.3.H.sub..sub.2 O: C,
57.9;H, 6.1; N, 18.75, Found: C, 57.7; H, 5.8; N, 18.5.
EXAMPLE 71
4-4-(4-Pyridyl)piperazin-1-yl!quinolin-6-yl!oxyacetic acid
To a solution of methyl
4-4-(4-pyridyl)piperazin-1-yl!quinolin-6-yloxyacetate (146 mg) in
methanol (5 ml) was added 2N sodium hydroxide (0.7 ml). The mixture was
stirred for 3 hours before evaporation to dryness. The resulting gum was
dissolved in water (3 ml) and acidified with acetic acid. This was
transfered to a reverse phase hplc column (Dynamax C18 83-201-C 60A) and
eluted with 0.1% TFA in water/acetonitrile. The pure fractions, on freeze
drying, gave the title compound (261 mg) as a solid: NMR (d.sub.6 DMSO)
.delta. 3.9-4.1(m,8H), 4.9(s,2H), 7.15(d,1H), 7.2(d,2H), 7.45(d,1H),
7.7(dd,1H), 8.0(d,1H), 8.35(d,2H), 8.65(d,1H); m/e 365(M+H).sup.+ ;
calculated for C.sub.20 H.sub.20 N.sub.4 O.sub.3.2TFA.0.5H.sub.2 O:
C,47.9; H, 3.8; N, 9.3. Found: C, 48.1; H, 3.6; N, 9.2.
The starting material was prepared as follows:
i) To a solution of methyl 4-bromoquinolin-6-yloxyacetate (169 mg) in
isopropanol (10 ml) was added 1-(4-pyridyl)piperazine (93 mg) followed by
2 drops of saturated ethereal HCl. The resulting mixture was refluxed for
18 hours. The mixture was filtered and concentrated. Purification by flash
column chromatography on silica, eluting with methanol/dichloromethane
(10% to 15% v/v in 1% increments) gave methyl
4-4-(4-pyridyl)piperazin-1-yllquinolin-6-yloxyacetate (74 mg) as a solid:
NMR (d.sub.6 DMSO) .delta. 3.2-3.4(m,4H), 3.6-3.7(m,4H), 3.75(s, 3H),
5.0(s,2H), 6.95(d,2H), 7.05(d, 1H), 7.25(d, 1H), 7.45(dd,1H), 7.9(d,1H),
8.25(d,2H), 8.6(d,1H); m/e 379(M+H).sup.+.
EXAMPLE 72
0:6 Mixture of isopropyl
2-4-(4-pyridyl)piperazin-1-yl!-quinolin-6-yloxyacetate and methyl
2-4-(4-pyridyl)piperazin-1-yl!oxyacetate
In a similar manner to Example 71i) the title mixture of compounds was
obtained. NMR (d.sub.6 DMSO) .delta. 1.2(d,4H, 0.6 isopropyl ester),
3.5-3.6(m,4H), 3.7(s,1.2H, 0.4 methyl ester), 3.73-3.85(m,4H), 4.8 and
4.85(s, 2H), 5.0(m,0.6 isopropyl ester), 6.9-7.0(m,2H),7.15-7.35(m,3H),
7.55(d, 1 H), 8.0(dd, 1 H), 8.1 5-8.25(m,2H); m/e 427/429(M+H).sup.+.
EXAMPLE 73
2-4-(4-Pyridyl)piperazin-1-yl!quinolin-6-yloxyacetic acid
To a solution of the product of Example 72 (145 mg) in methanol (5 ml) was
added 2N sodium hydroxide (0.7 ml). The mixture was stirred for 3 hours
before evaporating to (dryness. The resulting gum was dissolved in water
(3m1) and acidified with acetic acid. The resulting precipitate was
filtered and washed with water to give the title compound (47 mg): NMR
(d.sub.6 DMSO) .delta. 3.6-3.7(m,4H), 3.8-3.9(m,4H), 4.75(s,2H),
7.0(d,2H), 7.15(d,1 H), 7.2-7.3(m,2H), 7.55(d,1H), 8.0(d,1H), 8.25(d,2H);
m/e 365(M+H).sup.+ ; calculated for C.sub.20 H.sub.20 N.sub.4
O.sub.3.0.25H.sub.2 O : C,65.1; H. 5.6; N, 15.2. Found: C, 65.1; H, 5.4;
N, 15.0.
EXAMPLE 74
3-6-4-(4-Pyridyl)piperazin-1-yl!pyrid-2-yl!carboxamidopropionic acid
To a solution of isoamyl
3-6-4-(4-pyridyl!pipazin-1-yl!-pyrid-2-yl!carboxamidopropionate (140 mg)
in methanol (10 ml) was added 1N sodium hydroxide and the resulting
solution was stirred for 18 hours. The mixture was filtered and the
solvent was removed by evaporation to give the title compound as a white
solid: NMR (d.sub.6 DMSO+CD.sub.3 COOD) .delta. 2.5-2.6(m,2H), 3.55(t,2H),
3.8(s,8H), 6.9(d,1H), 7.05(d,2H), 7.35(d, IH), 7.6-7.7(m,1H), 8.15(d,2H);
m/e 356(M+H).sup.+.
The starting material was prepared as follows:
i) A suspension of 2,6-dibromopyridine (19 g) in diethylether (200 ml) was
added to a mixture of n-butyl lithium (130 ml of a 1.6M solution in
hexane) and diethylether (200 ml) cooled to -50.degree. C. The resulting
solution was stirred at -50.degree. C. for 10 minutes before pouring onto
a slurry of diethyl ether (100 ml) and dry-ice. The mixture was allowed to
warm to room temperature and filtered. The resulting solid was dissolved
in 2N sodium hydroxide (350 ml) and extracted with diethyl ether
(2.times.300 ml). The aqueous layer was separated and acidified with 2N
hydrochloric acid. The resulting precipitate was filtered and washed with
water to give 6-bromo-2-pyridine carboxylic acid (7.25 g): NMR (d.sub.6
DMSO) .delta. 7.69(d,1H), 7.95(d, 1H), 8.05(dd, 1H); m/e 202(M+H).sup.+.
ii) In a similar manner to Example 69 but starting from 6-bromo-2-pyridine
carboxylic acid was prepared methyl
3-(6-bromopyridin-2-carboxamido)propionate; NMR (d.sub.6 DMSO) .delta.
2.65(t,2H), 3.5-3.6(m,2H), 3.6(s,3H), 7.7-8.05(m,3H), 8.7(1H); m/e
287/289(M+H).sup.+ Br pattern.
iii) To a solution of the product of step ii) (770 mg) in isoamyl alcohol
(2.5 ml) was added 1-(4-pyridyl)piperazine (540 mg) and 2 drops of
saturated ethereal HCl. The resulting mixture was refluxed for 18 hours.
The mixture was concentrated and purified by flash column chromatography
on silica, eluting with methanol/dichloromethane (3:97 v/v), to give
isoamyl 3-6-4-(4-pyridyl)piperazin-1-yl!pyrid-2-yl!carboxamidopropionate
as a gum: NMR (d.sub.6 DMSO) .delta. 1.25-1.35(m,6H), 1.4-1.7(m,3H),
2.6(t,2H), 3.35-3.6(m,8H), 3.7-3.75(m,2H), 4.05(t,2H), 6.85(d,2H),
7.05(d,1H), 7.3(d,1H), 7.7(dd, 1H), 8.2(d,2H), 8.6(t,1H), m/e
426(M+H).sup.+.
EXAMPLE 75
4-4'-N-Methyl-N-(4-pyridyl)!aminomethyl!biphenyloxyacetic acid
To a solution of Methyl
4-4'-N-methyl-N-(4-pyridyl)!aminiomethyl!-biphenyloxyacetate (50 mg) in
methanol (5 ml) was added 1N sodium hydroxide (0.45 ml) and the resultlng
mixture was stirred for 18 hours. The resulting precipitate was filtered
to give the title compound (29 mg); NMR (d.sub.6 DMSO) .delta. 2.9(s,3H),
4.05(s,2H), 5.35(s,2H), 6.8-6.95(m,4H), 7.35-7.55(dd,4H), 7.6(d,2H),
8.2(d,1H), 8.45(d,IH); m/e 349(M+H).sup.+ ; calculated for C.sub.21
H.sub.20 N.sub.2 O.sub.3.2.25H.sub.2 O : C,64.9; H, 6.05; N, 7.2. Found:
C, 65.2; H, 6.4; N, 7.2.
The starting material was prepared as follows:
i) To a solution of 4-hydroxy-4-biphenylcarboxylic acid (2.14 g) in
tetrahydroftiran (25 ml) under an argon atmosphere was added slowly 1M
borane-THF complex (50 ml). The resulting mixture was stirred for 18 hours
before the addition of ethyl acetate (10 ml) and water (100 ml). The
resulting mixture was acidified with 2N hydrochloric acid and stirred for
30 minutes. The aqueous layer was extracted with ethyl acetate
(2.times.100 ml). The organic extracts were combined, dried (MgSO.sub.4)
and evaporated . Recrystallisation from a small volume of ethyl acetate
gave 4-hydroxy-4-biphenylmethanol (580 mg): NMR (d.sub.6 DMSO) .delta.
4.5(s,2H), 6.85(d,2H), 7.35(d,2H), 7.45-7.55(dd,4H), 9.45(s,1H); m/e
201(M+H).sup.+.
ii) To a solution of 4-hydroxy-4-biphenylmethanol (580 mg) in acetone (15
ml) was added anhydrous potassium carbonate (1.2 g) followed by methyl
bromoacetate (0.3 ml). The resulting mixture was stirred for 72 hours and
filtered. The solvent was removed by evaporation to give a solid which was
recrystallised from ethyl acetate to give methyl
4-(4'-hydroxymethyl)biphenyloxyacetate (316 mg); NMR (d.sub.6 DMSO)
.delta. 3.7(s,3H), 4.5(s,2H), 4.85(s,2H), 7.0(d,2H), 7.35(d,2H),
7.5-7.6(dd,4H); me 273(M+H).sup.+
iii) To a solution of the product from step ii) (300 mg) in dichloromethane
(15 ml) cooled to 5.degree. C. was added triethylamine (0.17 ml) followed
by methanesulphonyl chloride (0.19 ml). The resulting mixture was stirred
for 72 hours. Water (10 ml) was added and the mixture was extracted with
dichloromethane (3.times.5 ml). The organic extracts were combined, dried
(MgSO4) and evaporated to give a gum. Purification by flash column
chromatography on silica, eluting with ethyl acetate/hexanie (25:75 v/v)
gave methyl 4-(4'-chloromethyl)biphenyloxyacetate (230 mg) as a solid: NMR
(d.sub.6 DMSO) .delta. 3.75(s,3H), 4.8(s,2H), 4.85(s,2H), 7.05(d,2H),
7.5(d,2H), 7.6-7.65(dd,4H); m/e 290 M.sup.+.
iv) To a solution of 4-methylaminopyridine (142 mg) in acetonitrile (5 ml)
was added slowly a solution of the product of step iii) (230 mg) in
acetonitrile (5 ml). Tricthylaminie (0.18 ml) was added and the resulting
mixture was stirred for 72 hours. The mixture was partitioned between
water (20 ml) and dichloromethane (50 ml). The organic layer was
separated, dried (MgSO.sub.4) and evaporated to give a solid, which was
recrystallised firom isopropanol to give methyl
4-4'-N-methyl-N-(4-pyridyl)aminomethyl!biphenyloxyacetate (50 mg): NMR
(d.sub.6 DMSO) .delta. 2.9(d,3H), 3.7(s,3H), 4.85(s,2H), 5.4(s,2H),
6.85-6.95(m,2H),7.0(d,2H), 7.45(d,2H), 7.55-7.7(dd,4H), 8.25(d, 1H),
8.5(d, 1H); m/e 363(M+H).sup.+.
EXAMPLE 76
5-4-(4-Pyridyl)piperazin-1-yl!methylene!naphth-2-yloxyacetic acid
In a similar manner to Example 67, but starting from methyl
5-4-(4-pyridyl)piperazin-1-yl!methylene!naphth-2-yloxyacetate was
prepared the title compound: NMR (d.sub.6 DMSO) .delta. 2.75(m,4H),
3.7(m,4H), 4.1 (s,2H), 4.8(s,2H), 7.15-7.5(m,6H), 7.8(d,1H),
8.2-8.3(m,3H); m/e 378(M+H).sup.+.
The starting material was prepared as follows:
i) A solution of 6-methoxy-1-tetralone (15 g) in diethyl ether (250 ml) was
added slowly to a mixture of methyl magnesium iodide (37 ml of a 3M
solution in diethyl ether) and diethyl ether (100 ml) whilst maintainiig
the temperature below 10.degree. C.. After stirring at 5.degree. C. for 30
minutes, the mixture was refluxed for 2 hours. The reaction was quenched
with saturated ammoniumn chloride. The organic layer was separated
dried(MgSO.sub.4) and evaporated. Purification by flash column
chromatography, eluting with ethyl acetatc/hexane (1:99 v/v) gave
1-methyl-7-methoxy-1,2-dehydrodecalin (11.58 g) as an oil: NMR (d.sub.6
DMSO) .delta. 1.95(m,3H), 2.1-2.25(m,2H), 2.7(d,2H), 3.75(s,3H),
5.65-5.75(m,1H), 6.7-6.8(m,2H), 7.1(d, 1H); m/e 175(M+H).sup.+.
ii) 2,3-Dichloro 5,6 dicyano-1,4 benzoquinone (17.85 g) was added in one
portion to a solution of the product from step i) (11.56 g) in toluene
(500m1). After stirring for 1 hour the mixture was filtered and an equal
volume of hexane was added. The diluted filtrate was passed down a short
alumina column. Removal of the solvent gave 6-methoxy-1-methylnaphthalene
(6.4 g) as an oil: NMR (d.sub.6 DMSO) .delta. 2.6(s,3H), 3.7(s,3H),
7.15-7.25(m,2H), 7.3-7.35(m,2H), 7.65(d,1H), 7.9(d,1H); m/e
173(M+H).sup.+.
iii) To a solution of 6-methoxy-1-methylnaphthalene (6.4 g) in
dichloromethanie (500 ml), cooled to -60.degree. C., was added boron
tribromide (45 ml of a 1M solution in dichloromethane). The resulting
mixture was stirred at -60.degree. C. for 3 hours. The reaction was
quenched with water (500 ml) and extracted with dichloromethane (2x500
ml). The organic extracts were combined, dried (MgSO.sub.4) and evaporated
to give a solid. Purification by flash column chromatography on silica,
eluting with ethyl acctate/hexane (5:95 v/v) gave 6-methyl-2-naphthol
(3.76 g) as a white solid. This was used without further characterisation.
iv) To a solution of 6-methyl-2-naphthol (3.15 g) in acetone (100 ml) was
added anhydrous potassium carbonate (6.0 g) followed by methyl
bromoacetate (2.0 ml). The mixture was stirred for 18 hours and then
filtered. The solvent was removed by evaporation to give an oil.
Purification by flash column chromatography on silica, eluting with ethyl
acetate/hexane (5:95 v/v) gave methyl 2-(5-methyl)naphthoxyacetate (3.8 g)
as a white solid: NMR (d.sub.6 DMSO) .delta. 2.6(s,3H), 3.7(s,3H),
4.9(s,2H), 7.15-7.4(m,4H), 7.65(d,1H), m/e 23 1(M+H).sup.+.
v) To a solution of the product from step iv) (1.5 g) in carbon
tetrachloride (100 ml) was added N-bromosuccinimide (1.16 g) followed by a
catalytic amount of AIBN. The resulting mixture was refluxed for 2 hours.
The solvent was removed by evaporation to give an oil, which was purified
by flash column chromatography on silica eluting with ethyl acetate/hexane
(5:95 v/v) to give methyl 2-(5-bromomethyl)naphthoxyacetate (1.16 g) as a
gum: NMR (d.sub.6 DMSO) .delta. 3.75(s,3H), 4.95(s,2H), 5.2(s,2H),
7.3-7.6(m,4H), 7.8(d,1H), 8.15(d,1H); m/e 309/311 (M+H).sup.+ Br pattern.
vi) In a similar manner to Example 66, but starting from the product of
step v) was prepared methyl
5-4-(4-pyridyl)piperazin-1-yl!methylenelnaphth-2-yloxyacetate: NMR
(d.sub.6 DMSO) .delta. 3.2-3.35(m,8H), 3.7(s,3H), 3.9(s,2H), 4.9(s,2H),
6.8(d,2H), 7.2-7.45(m,4H), 7.75(d, 1H), 8.15(d,2H), 8.25(d, 1H); mie
392(M+H).sup.+.
EXAMPLE 77
4-4-(4-Pyridyl)piperazin-1-yl!methylene!cinnamic acid
.sup.t Butyl 4-4-(4-pyridyl)piperazin-1-yl!methylene!cinnamate (200 mg)
was stirred in trifluoroacetic acid (5 ml) for 2 hours. The solvent was
removed by evaporation and the resulting oil was titriated with anhydrous
ether to give the title compound (210 mg) as a white solid: NMR (d.sub.6
DMSO) .delta. 3.05-3.25(m,4H), 3.7-4.1(bm,4H), 4.25(s,2H), 6.6(d,1H),
7.25(d,2H), 7.5(d,2H), 7.6(d,1H), 7.75(d,2H), 8.35(d,2H); m/e
324(M+H).sup.+ ; calculated for C.sub.19 H.sub.21 N.sub.3
O.sub.2.2CF.sub.3 COOH.0.5H.sub.2 O: C, 49.5; H, 4.25; N, 7.4. Found: C,
49.1; H, 4.2; N, 7.1.
The starting material was prepared as follows:
i) In a similar to Example 66, but starting from .sup.t butyl 4-bromomethyl
cinnamate was prepared .sup.t butyl
4-4-(4-pyridyl)piperazin-1-yl!methylenel cinnamate: NMR (d.sub.6 DMSO)
.delta. 1.45(s,9H), 3.55(s,2H), 6.5(d,1H), 6.8(d,2H), 7.35(d,2H),
7.55(d,1H), 7.65(d,2H), 8.15(d,2H).
EXAMPLE 78
Dimethyl
4-2-4-(4-pyridyl)piperazin-1-yl)-2-methyl!acetyl!-1,2-diphenoxydiacetate
In a similar manner to Example 66, but starting from dimethyl
4-(2'-bromopropionyl)-phenylene-1,2-dioxy!diacetate was prepared the
title compound: NMR (d.sub.6 DMSO) .delta. 1.15(d,3H), 2.55-2.7(m,4H),
3.2-3.35(m,4H), 3.68(s,3H), 3.70(s,3H), 4.25(q,1H), 4.9(s,2H), 4.95(s,2H),
6.75(d,2H), 7.0(d,1H), 7.65(d,1H), 7.75(dd,1H), 8.15(d,2H); m/e
472(M+H).sup.+. The starting material was prepared as follows:
i) To a solution of 3,4 dihydroxypropiophenone (1.24 g) in DMF (1Smi) was
added anhydrous potassium carbonate (3.09 g) followed by methyl
bromoacetate (1.4 ml). The resulting mixture was stirred for 24 hours.
Water (50 ml) was added and the mixture was extracted with ethyl acetate
(3.times.100 ml) The organic extracts were combined, dried (MgSO.sub.4)
and evaporated to give a gum. Purification by flash column chromatography
on silica eluting with ethyl acetate/hexane (1:1 v/v) gave dimethyl
4-propionyl-phenylene-1,2-dioxydiacetate (1.79 g) as an oil: NMR (d.sub.6
DMSO) .delta. 1.05(t,3H), 3.0(q,2H), 3.7(s,6H), 4.9(s,2H), 4.95(s,2H),
7.05(d,d,1H), 7.45(d,1H), 7.6(dd,1H); m/e 311 (M+H).sup.+.
ii) To a solution of the product from step i) (1.79 g) in chloroform (15
ml) was added dropwise a solution of bromine (0.3 ml) in chloroform (5 ml)
and the resulting mixture was stirred for 3 hours. The solvent was removed
by evaporation to give a gum which was purified by flash column
chromatography on silica, eluting with ethyl acetate/hexane (2:3 v/v) to
give dimethyl 4-(2'-bromopropionyl)-phenylene-1,2-dioxy)diacetate (1.95
g), which solidified on standing: NMR (d.sub.6 DMSO) 8 1.75(d,3H),
3.7(s,6H), 4.9(s,2H), 4.95(s,2H), 5.8(q,1H), 7.05(d, 1H), 7.5(d, 1H),
7,7(dd, 1H); m/e 389/391 (M+H).sup.+ Br pattern.
EXAMPLE 79
4-2-(4-Pyridyl)piperazin-1-yl!-2-methyl!acetyl-1,2-diphenoxydiacetic acid
In a similar manner to Example 67, but starting from the product of Example
78 was prepared the title compound: NMR (d.sub.6 DMSO) .delta. 1.4(d,3H),
3.0-3.2(m,4H), 3.75-3.9(m,4H), 4.75.5.0(m, 1H), 4.8(s,2H), 4.85(s,2H),
7.05(d, 1H), 7.25(d,2H), 7.55(d, 1H), 7.75(dd, 1H), 8.3(d,2H); mle
444(M+H).sup.+. Calculated for C.sub.22 H.sub.25 N.sub.3
O.sub.7.2.25CF.sub.3 COOH.H.sub.2 O C, 44.3; H, 4.1; N, 5.85; TFA, 35.7.
Found C, 44.2; H, 3.9; N, 5.7; TFA, 36.2.
EXAMPLE 80
Methyl 2-4-(4-pyridyl)piperazin-1-yl!tetralone-6-oxyacetate
In a similar manner to Example 66, but starting from methyl
2-bromotetralone-6-oxyacetate was prepared the title compound: NMR
(d.sub.6 DMSO+CD.sub.3 COOD) .delta. 2.05-2.4(m,2H), 2.9-3.05(m,2H), 3.1
-3.25(m,4H), 3.6(s,3H), 3.75-3.9(m,4H), 4.05(dd,IH), 4.75(s,2H),
6.75(d,1H), 6.85(dd,1H), 7.05(d,2H), 7.85(d,1H), 8.1 (d,2H); m/e
396(M+H).sup.+. The starting material was prepared as follows:
i) A solution of 6-methoxy- 1-tetralone (5.0 g) in 48% hydrobromic acid (62
ml) was refluxed for 8 hours. The mixture was cooled, filtered and washed
with water (50 ml) to give 6-hydroxy-1-tetralone (3.91 g): NMR 5 (d.sub.6
DMSO) 1.9-2.05(m,2H), 2.4-2.55(m,2H), 2.8-2.9(m,2H), 6.65(d, 1H),
6.7(dd,1H), 7.75(d,1H), m/e 163(M+H).sup.+.
ii) To a solution of 6-hydroxy-1-tetralone (2.62 g) in acetone (50 ml) was
added anhydrous potassium carbonate (2.23 g) followed by methyl
bromoacetate (1.52 ml) and the resulting mixture was stirred for 18 hours.
The mixture was filtered and the solvent was evaporated to give a yellow
solid. Recrystallisation from ethyl acetate gave methyl
tetralone-6-oxyacetate (2.28 g): NMR (d.sub.6 DMSO) 6 1.95-2.05(m,2H),
2.45-2.55(m,2H), 2.9(t,2H), 3.7(s,3H), 4.9(s,2H), 6.85-6.9(m,2H),
7.8(d,1H); m/e 235(M+H).sup.+.
iii) To a solution of the product from step ii) (1.3 g) in chloroform (15
ml) was added dropwise a solution of bromine (0.29 ml) in chloroform (1
ml) and the resulting mixture was stirred for 4 hours. The solvent was
evaporated to give an oil. Purification by flash column chromatography on
silica, eluting with ethyl acetate/hexane (30:70 v/v) gave methyl
2-bromotetialone-6-oxyacetate (1.55 g) as an oil: NMR (d.sub.6 DMSO)
.delta. 2.3-2.6(m,2H), 2.9-3.1(m,2H), 3.7(s,3H), 4.9(s,2H), 4.9-5.0(m,1H),
6.9-7.0(m,2H), 7.9(d,1H); m/e 313/315(M+H).sup.+ Br pattern.
EXAMPLE 81
Methyl
2-S-(n-butylsulphonylamino)-3-4-3-1-(4-pyridyl)piperidin-4-yl!propoxy!p
henyl!propionate
Using a procedure similar to that described in Example 35, but starting
from the appropriate amino ester, the title compound was prepared; NMR
(d.sub.6 DMSO) 0.75(t,3H), 1.0-1.44(m,8H), 1.44-1.64(m, 1H), 1.75(brd,4H),
2.5-3.02(m,6H), 3.64(s,3H), 3.85-4.1 (m,5H), 6.81 (d,2H), 6.84(d,2H),
7.19(d,2H), 7.78(d, 1H), 8. 12(d,2H); mass spectrum (+ve FAB, MeOH/NBA):
518 (M+H).sup.+.
The starting material was prepared using similar procedures to those
described in Example 33. There was thus prepared the following
intermediates i) and ii) which were themselves prepared starting from
4-(4-hydroxypropylpiperidin- 1 -yl) pyridine iii).
i) Methyl 2-S-(benzyloxycarbonylamino)-3- 4- 3-1
-(4-pyridyl)piperidin-4-yl!-propoxy!phenyl!propionate; NMR (d.sub.6 DMSO)
1.18-1.24(m,2H), 1.3-1.43(m,2H), 1.44-1.65(m,1H), 1.65-1.83(m,4H),
2.7-2.88(m,3H), 2.96(dd,1H), 3.61(s,3H), 3.92(t,4H), 4.14-4.25(m, 1H),
4.98(s,2H), 6.8(d,2H), 6.82(d,2H), 7.14(d,2H), 7.2-7.4(m,5H), 7.74(d,1H),
8.12(d,2H); mass spectrum(+ve FAB, MeOH/NBA): 532(M+H).sup.+.
ii) Methyl 2-S-amino-3- 4-
3-1-(4-pyridyl)piperidin-4-yl!propoxy!phenyl!propionate;
NMR (d.sub.6 DMSO) 1.03-1.2(m,2H), 1.28-1.40(m,2H), 1.42-1.62(m, 1H),
1.64-1.80(m,4H), 2.65-2.9(m,4H), 3.58(s,3H), 3.45-3.6(m, 1 H),
3.85-3.98(mn,4H), 6.78(d,2H), 6.8(d,2H), 7.06(d,2H), 8.11 (d,2H); mass
spectrum(+ve FAB, MeOH/NBA): 398(M+H).sup.+.
iii) 4-(4-Hydroxypropylpiperidin-1-yl)pyridine.
A solution of N-(2-carbamoylethyl)-4-cyanopyr-idinium chloride (2.1 g) in
water (5 ml) was added dropwise to a stirred mixture of
4-hydroxypropylpiperidine (2.4 g), water (10 ml) and 2.5M sodium hydroxide
solution (4.6 ml) cooled in an ice-bath. The mixture was stirred at
0-5.degree. C. for 1 hour. 2.5M sodium hydroxide solution (7 ml) was added
and the mixture heated at reflux for 3 hours. The mixture was cooled in an
ice-bath and gummy solid separated out. The aqueous layer was decanted off
and the gummy solid dissolved in dichloromethane (75 ml). The solution was
washed with saturated sodium chloride solution (10 ml) and dried
(MgSO.sub.4). The solvent was removed by evaporation to give a gummy solid
(880 mg) which on trituration with ether gave a solid; NMR (d.sub.6 DMSO)
1.0-1.35(m,4H), 1.35-1.6(m,3H), 1.7(dd,2H), 2.70-2.88(dt,2H), 3.38(t,2H),
3.89(brd,2H), 4.35(brs, 1H), 6.78(d,2H), 8.1 (d,2H); mass
spectrum(Cl.sup.+): 221 (M+H).sup.+.
EXAMPLE 82
2-S-(n-Butylsulphonylamino)-3-4-3-1-(4-pyridyl)piperidin-4-yl!propoxy!ph
enyl!propionic acid
Using a similar procedure to that described in Example 34, but starting
from the product of Example 81, the title compound was obtained as an
amorphous solid; NMR (d.sub.6 DMSO/CD.sub.3 CO.sub.2 D) 0.73(t,3H),
1.0-1.5(m,8H), 1.55-1.85(m,5H), 2.54-2.78(m,3H), 2.9-3.2(m,3H),
3.8-3.98(m,3H), 4.15(brd,2H), 6.8(d,2H), 7.09(d,2H), 7.15(d,2H),
8.1(d,2H); mass spectrum(+ve FAB, MeOH/NBA): 504(M+H).sup.+ ;
microanalysis found C,60.3; H,7.2; N,7.9%; C.sub.26 H.sub.37 N.sub.3
O.sub.5 S.H.sub.2 O requires C,59.9; H,7.5; N,8.1%.
EXAMPLE 83
Methyl
2-S-(butylsulphonylamino)-3-4-4-1-(4-pyridyl)piperidin-4-yl!-butoxy!phe
nyl!propionate
Using, a similar procedure to that described in Example 35, but starting
from the appropriate amino ester, the title compound was prepared; NMR
(CDCl.sub.3) 0.87(t,3H), 1.14-1.4(m,6H), 1.42-1.7(m,5H), 17-1.9(m,4H),
2.7-3.18(m,6H), 3.78(s,3H), 3.9(brd,2H), 3.93(t,2H), 4.32(brs,1H),
4.82(brs,1H), 6.66(d,2H), 6.83(d,2H), 7.09(d,2H), 8.22(d,2H); mass
spectrum(+ve FAB, McOH/NBA): 532 (M+H).sup.+.
The starting material was prepared using similar procedures to those
described in Examples 33 and 81iii). There was thus prepared the following
intermediates:
i) 4-(4-hydroxybutylpipeidin-1-yl)pyridine; NMR (d.sub.6 DMSO)
0.97-1.58(m,9H), 1.7(dd,2H), 2.78(dt,2H), 3.38(m,2H), 3.88(brd,2H),
4.29(t, 1H), 6.78(d,2H), 8.10(d,2H); mass spectrum(Cl.sup.+):
235(M+H).sup.+.
ii) Methyl
2-S-(benzylcarbonylamino)-3-4-4-1-(4-pylridyl)piperidin-4-yl!butoxy!phe
nyl!propionate; NMR (d.sub.6 DMSO) 1.0-1.35(m,4H), 1.35-1.60(m,3H),
1.62-1.80(m,4H), 2.8(dt,3H), 2.96(dd,1H), 3.62(s,3H), 3.85-3.97(m,4H),
4.15-4.28(m,1H), 4.99(s,2H), 6.78(d,2H), 6.81(d,2H), 7.13(d,2H),
7.2-7.4(m,5H), 7.74(d,IH), 8.11(d,2H); mass spectrum(Cl.sup.+):
546(M+H).sup.+.
iii) Methyl 2-S-amino-3-4- 4- 1-(4-pyridyl)-piperidin-4-yl!butoxy
!phenyl!propionate; NMR (d.sub.6 DMSO) 1.05-1.35(m,4H), 1.35-1.58(m,3H),
1.6-1.8(mn,4H), 2.65-2.9(m,4H), 3.51(t,1H), 3.58(s,3H), 3.8-3.98(m,4H),
6.78(dd,2H), 6.8 1(d,2H), 7.05(d,2H), 8.1(dd,2H); mass spectrum(Cl.sup.+):
412(M+H).sup.+.
EXAMPLE 84
2-S-(n-Butylsulphonylamino)-3-4-4-1-(4-pyridyl)piperidin-4-yl!butoxy!phe
nyl!propionic acid
Using a similar procedure to that described in Example 34 but starting fiom
the product of Example 83, thc title compound was obtained as an amorphous
solid; NMR (d.sub.6 DMSO) 0.78(t,3H), 1.0-1.6(m,l 1H), 1.6-1.82(brt,4H),
2.5-3.04(m,6H), 3.8-4.0(m,5H), 6.8(m,4H), 7.19(d,2H), 8.1(brd,2H); mass
spectrum(+ve FAB,MeOH/NBA): 518(M+H).sup.+ ; microanalysis found C,62.4;
H,7.8; N,7.9%; C.sub.27 H.sub.39 N.sub.3 O.sub.5 S requires C,62.6; H,7.6;
N,8.1%.
EXAMPLES 85-87
Using a procedure similar to that described in Example 35, but starting,
fiom the appropriatc substituted suliphonyl chloride and methyl
2-S-amino-3-4-2-1-(4-pyridyl)piperidin-4-yl!ethoxylphenyl!propionate
there was obtained the following compounds:
EXAMPLE 85
Methyl
2-S-(methsulphonylamino)-3-4-2-1-(4-pyridyl)piperidin-4-yl!ethoxy!pheny
l!propionate
NMR (d.sub.6 DMSO) 1.08-1.34(m,2H), 1.6-1.85(m,5H), 2.6(s,3H),
2.7-3.0(m,4H), 3.63(s,3H), 3.84-4.2(m,5H), 6.80(d,2H), 6.85(d,2H),
7.18(d,2H), 8.12(d,2H); mass spectrum(+ve FAB, McOH/NBA): 462(M+H).sup.+.
EXAMPLE 86
Methyl
2-S-(benzylsulphonylamino)-3-4-2-1-(4-pyridyl)piperidin-4-yl!ethoxy!phe
nyl!propionate
NMR (d.sub.6 DMSO) 1.05-1.28(m,2H), 1.57-1.82(m,5H), 2.68-2.95(m,4H),
3.58(s,3H), 3.8-4.15(m,7H), 6.79(d,2H), 6.88(d,2H), 7.12(d,2H),
7.17(m,2H), 7.3(m,3H), 7.79(brd, 1H), 8.1(d,2H); mass spectrum(+ve FAB,
MeOH/NBA): 538(M+H)+.
EXAMPLE 87
Methyl
2-S-(4-methylphenylsulphonylamino)-3-4-2-1-(4-pyridyl)piperidin-4-yl!et
hoxy!phenyl!propionate
NMR (d.sub.6 DMSO) 1.1-1.33(m,2H), 1.6-1.88(m,5H), 2.35(s,3H),
2.6-2.75(dd,1H), 2.75-2.92(m,3H), 3.38(s,3H), 3.8-4.1(m,5H), 6.76(d,2H),
6.81(d,2H), 7.0(d,2H), 7.28(d,2H), 7.47(d,2H), 8.12(d,2H), 8.32(d, 1H);
mass spectrum(+ve FAB, MeOH/NBA): 538(M+H).sup.+.
EXAMPLES 88-90
Following the method of Example 34, but using the products of Examples
85-87, there was obtained the following compounds:
EXAMPLE 88
2-S-(Methylsulphonylamino)-3-4-2-1-(4-pyridyl)piperidin-4-yl!ethoxy!phen
yl!propionic acid
NMR (d.sub.6 DMSO) 1.05-1.35(m,2H), 1.6-1.95(m,5H), 2.61(s,3H),
2.65-3.1(m,4H), 3.88-4.1(m,5H), 6.84(d,2H), 6.9(d,2H), 7.18(d,2H),
8.14(d,2H); mass spectrum(+ve FAB, MeOH/NBA): 448(M+H).sup.+.
EXAMPLE 89
2-S-(Benzylsulphonylamino)-3-4-2-1-(4-pyridyl)piperidin-4-yl!ethoxy!phen
yl!propionic acid
NMR (d.sub.6 DMSO/CD.sub.3 CO.sub.2 D) 1.07-1.35(m,2H), 1.60-1.88(m,5H),
2.7-3.2(m,4H), 3.85-4.25(m,7H), 6.87(d,2H), 7.1 (d,2H), 7.13-7.45(m,7H),
8.15(d,2H); mass spectrum(+ve FAB,MeOH/NBA): 524(M+H).sup.+ ;
microanalysis found C,61.8; H,6.8; N,7.6%; C.sub.28 H.sub.33 N.sub.3
O.sub.5 S.H.sub.2 O requires C,62. 1; H,6.5; N,7.8%.
EXAMPLE 90
Lithium
2-S-(4-methylphenylsulphonylamino)-3-4-2-1-(4-pyridyl)piperidin-4-yl!et
hoxy!phenyl!propionate
NMR (d.sub.6 DMSO/CD.sub.3 CO.sub.2 D) 1.15-1.38(m,2H), 1.67-1.78(m,2H),
1.82-2.0(m,3H), 2.36(s,3H), 2.65-2.8(dd, 1H), 2.85-2.95(dd, 1H),
3.14(t,2H), 3.78(m, 1H), 4.0(t,2H), 4.18(d,2H), 6.77(d,2H), 7.04(d,2H),
7.1 1(d,2H), 7.24(d,2H), 7.51(d,2H), 8.15(d,2H); mass spectrum(+ve FAB,
MeOH/NBA): 536(M+Li).sup.+ ; microanalysis found C,63.2; H,6.5; N,7.9%;
C.sub.28 H.sub.32 N.sub.3 O.sub.5 SLi requires C,63.5; H,6.1; N,7.9%.
EXAMPLE 91
Methyl
2-S-(pentanoylamino)-3-4-2-1-(4-pyridyl)piperidin-4-yl!ethoxy!phenyl!pr
opionate
Valeryl chloride (0.25 ml) was added dropwise to a solution of methyl
2-S-amino-3-4-2- 1-(4-pyridyl)piperidin-4-yl!ethoxy !phenyl!propionate
(640 mg) and triethylamine (0.7 ml) in dichloromethane (17 ml) at ambient
temperature. The reaction mixture was stirred for 5 hours and then diluted
with dichloromethane (20 ml) and washed with water (20 ml), saturated
sodium chloride solution (10 ml) and dried (MgSO.sub.4). The solvent was
evaporated and the residue purified by flash chromatography eluting with
methanol/dichloromethane (1:9 v/v) to give the title compound (660 mg) as
a gum; NMR (d.sub.6 DMSO) 0.81 (t,3H), 1.05-1.3(m,4H), 1.3-1.45(m,2H),
1.60-1.85(m,5H), 2.04(t,2H), 2.7-3.0(m,4H), 3.6(s,3H), 3.92(d,2H),
3.99(t,2H), 4.35-4.48(m,1H), 6.8(d,2H), 6.83(d,2H), 7.11(d,2H),
8.12(d,2H), 8.18(d,1H); m/e +ve FAB,MeOH/NBA): 468(M+H).sup.+.
EXAMPLE 92
Methyl
2-S-(pentanoylamino)-3-4-1-(4-pyridyl)piperidin-4-yl!methoxyphenyl!propi
onate
Using a procedure similar to that described in Example 91, but starting
from the appropriate amino ester, the title compound was prepared, NMR
(d.sub.6 DMSO) 0.8(t,3H), 1.05-1.45(m,6H), 1.83(dd,2H), 1.9-2.1 (m, 1H),
2.04(t,2H), 2.7-3.0(m,4H), 3.59(s,3H), 3.82(d,2H), 3.96(d,2H),
4.35-4.48(m, 1H), 6.80(d,2H), 6.83(d,2H), 7. 10(d,2H), 8.12(d,2H), 8.17(d,
11H); mass spectrum(+vc FAB, MeOH/NBA): 454(M+H).sup.+.
EXAMPLE 93
2-S-(Pentanoylamino)-3-4-2-1-(4-pyridyl)piperidin-4-yl!ethoxy!phenyl!pro
pionic acid
Using a procedure similar to that described in Example 34, but starting
from the product of Example 91, the title compound was prepared, NMR
(d.sub.6 DMSO) 0.8(t,3H), 1.08-1.3(m,4H), 1.3-1.45(m,2H), 1.6-1.87(mn,5H),
2.05(t,2H), 2.7-3.05(m,4H), 3.9-4.05(m,4H), 4.3-4.43(m, 1 H), 6.82(d,2H),
6.85(d,2H), 7.11 (d,2H), 7.97(d, 1H), 8.12(brd,2H); mass spectrum(+ve FAB,
MeOH/NBA): 454(M+H).sup.+ ; microanalysis found C,63.1 H,7.8; N,8.3%;
C.sub.26 H.sub.35 N.sub.3 O.sub.4.2H.sub.2 O requires C,63.8; H,8.0;
N,8.6%.
EXAMPLE 94
2-S-(Benzyloxycarbonylamino)-3-4-2-1-(4-pyridyl)piperidin-4-yl!ethoxy!ph
enyl!propionic acid
Using a procedure similar to that described in Example 34, but starting
from the product of Example 35i), the title compound was prepared, NMR
(d.sub.6 DMSO) 1.1-1.35(m,2H), 1.6-1.9(m,5H), 2.65-3. 1(m,4H1),
3.85-4.2(m,5H), 4.96(s,2H), 6.75-6.9(m,4H), 7.14(d,2H), 7.2-7.35(m,5H),
7.5(d, 1H), 8.1 (d,2H); mass spectrum(+ve FAB, MeOH/NBA): 504(M+H).sup.+.
EXAMPLE 95
Methyl-2-S-(n-butylsulphonylamino)-3-3-(N-methyl-N-4-pyridyl)aminopropoxy!
phenylpropionate
Using a procedure similar to that described in Example 33, but starting
from methyl
2-S-amino-3-3-(N-methyl-N-4-pyridyl)aminopropoxy!phenylpropionate, the
title compound was prepared, NMR (CDCI.sub.3) 0.89(t,3H), 1.25-1.4(m,2H),
1.55-1.75(m,2H), 2.0-2.15(m,2H), 2.80(dd,2H), 2.9-3.15(m,2H), 3.05(s,3H),
3.63(t,2H), 3.77(s,3H), 3.95(t,2H), 4.28-4.38(m,1H), 6.57(d,2H),
6.80(d,2H), 7.10(d,2H), 8.14(d,2H); mass spectrum (Cl.sup.+);
464(M+H).sup.+.
The starting material was prepared as follows:
i) Using a procedure similar to that described in Example 33i), but
starting from N-methyl-N-(4-pyridyl)aminopropanol and
N-t-butyloxycarbonyl-S-tyrosine methyl ester, there was obtained, methyl
2-S-(t-butyloxycarbonylamino)-3-3-N-methyl-N-(4-pyridyl)aminopropoxy!phen
yl propionate, as a gum, NMR (CDCl.sub.3) 1.43(s,9H), 2.0-2.15(mi,2H),
3.04(s,3H), 2.95-3.10(m,2H), 3.62(t,2H), 3.73(s,3H), 3.98(t,2H), 4.54(brd,
1H), 4.98(brd, 1H), 6.56(d,2H), 6.80(d,2H), 7.04(d,2H), 8.17(d,2H).
ii) The product from step i) (500 mg) and 5M methaniolic hydrochloric acid
solution (4 ml) was stirred at ambient temperature for 16 hours. The
solvent was evaporated to give the corresponding amino compound as the
dihydrochloride salt which was used without further purification.
EXAMPLE 96
2-S-(n-Butylsulphonylamino)-3-3-(N-4-pyridyl-N-methyl)aminopropoxylphenyl
propionic acid
Using a procedure similar to that described in Example 34, but starting
from the product of Example 95, the title compound was prepared, NMR
(d.sub.6 DMSO/CD.sub.3 CO.sub.2 D) 0.8(t,3H), 1.1-1.28(m,2H),
1.28-1.55(m,2H), 2.0-2.1 5(m,2H), 2.6-2.8(m,3H), 2.93-3.08(dd,1H),
3.18(s,3H), 3.75(t,2H), 3.9-4.05(m,3H), 6.86(d,2H), 7.0(d,2H), 7.2(d,2H),
8.15(d,2H); mass spectrum (+ve FAB,MeOH/NBA): 450(M+H).sup.+ ;
microanalysis found C,53.9; H,6.9; N,8.4%; C.sub.22 H.sub.31 N.sub.3
O.sub.5 S.2H.sub.2 O requires C,54.4; H,7.2; N,8.6%.
EXAMPLE 97
Methyl
3-(n-butylsulphonylamino)-3-4-1-(4-pyridyl)piperidin-4-yl!-methoxyphenyl
!propionate
Using a procedure similar to that described in Example 33, but starting
from methyl
3-amino-3-4-1-(4-pyridyl)piperidin-4-yl!methoxyphenyl!propionate,
dihydrochloride, the title compound was prepared; NMR (CDCl.sub.3)
0.84(t,3H), 1.2-1.4(m,2H), 1.4-1.55(m,2H), 1.55-1.75(m,2H), 1.97(brd,2H),
2.02-2.2(m,1H), 2.65-2.85(m,2H), 2.88(d,2H), 3.0(dt,2H), 3.67(s,3H),
3.84(d,2H), 4.0(brd,2H), 4.85(q,1H), 5.40(d,1H), 6.71(d,2H), 6.86(d,2H),
7.27(d,2H), 8.25(d,2H); mass spectrum(+ve FAB,MeOH/NBA): 490(M+H).sup.+.
The starting material was prepared as follows:
i) Thionyl chloride (4.3 ml) was added to methanol (50 ml) cooled in an
ice-salt bath. 3-Amino-3-(4-hydroxyphenyl)propionic acid (9.7 g) was added
and the mixture allowed to reach ambient temperature and then refluxed for
2 hours. The solvent was removed by evaporation in vacuo to give a gummy
solid (12.8 g) which was used without further purification. A solution of
di-t-butyldicarbonate (5.8 g) in dichloromethane (50 m) was added to a
stirred mixture of the gummy solid (5.75 g) and potassium hydrogen
carbonate (6.2 g) in water (20 ml). The mixture was stirred at ambient
temperature for 4 hours. The organiic layer was separated and washed with
water (10 ml), 1M hydrochloric acid solution (10 ml), saturated sodium
hydrogen carbonate solution (10 ml), water (10 ml) and dried (MgSO.sub.4).
The solvent was evaporated to give methyl
3-(t-butyloxycarbonylamino)-3-(4-hydroxyphenyl)propionate as a solid; m.p.
119.degree.-120.degree. C.; NMR (d.sub.6 DMSO) 1.34(s,9H),
2.54-2.78(m,2H), 3.53(s,3H), 4.7-4.9(q, 1H), 6.67(d,2H), 7.08(d,2H),
7.28(brd, 1H), 9.24(brs,1H).
ii) Using a procedure similar to that described in Example 33i), but using
the product of step i), methyl
3-(t-butyloxycarbonylamino)-3-4-1-(4-pyridyl)piperidin-4-yl!-methoxyphen
yl!propionate was prepared as a gum; NMR (CDCl.sub.3) 1.33-1.55(m,2H),
1.44(s,9H), 1.95(brd,2H), 1.95-2.15(m, 1 H), 2.7-3.0(m,4H), 3.61 (s,3H),
3.80(d,2H), 3.95(brd,2H), 4.95-5.1(m,1H), 5.25-5.40(m,1H), 6.68(d,2H),
6.85(d,2H), 7.2(d,2H), 8.25(d,2H).
iii) The product of step ii) (550 mg) and 5M methanolic hydrochloric acid
solution (4 ml) was stirred at ambient temperature for 18 hours. The
solvent was evaporated to give methyl 3-amino-3-4-1
-(4-pyridyl)piperidin-4-yl!methoxyphenyl!propionate dihydrochloride as a
foam; NMR (d.sub.6 DMSO/CD.sub.3 CO.sub.2 D) 1.23-1 45(m,2H),
1.92(brd,2H), 2.05-2.25(m, 1H), 3.0-3 25(m,4H), 3.52(s,3H), 3.85(d,2H),
4.2(brd,2H), 4.54(t,1H), 6.92(d,2H), 7.1(d,2H), 7.39(d,2H), 8.10(d,2H).
EXAMPLE 98
3-(n-Butylsulphonylamino)-3-4-1-(4-pyridyl)piperidin-4-yl!methoxyphenyl!p
ropionic acid
Using a procedure similar to that described in Example 34, but using the
product of Example 97, the title compound was prepared; NMR (d.sub.6
DMSO/CD.sub.3 CO.sub.2 D) 0.78(t,3H), 1.05-1.3(m,2H), 1.3-1.57(m,4H),
1.98(brd,2H), 2.1 -2.33(m, 1 H), 2.45-2.85(m,4H), 3.25(t,2H), 3.89(d,2H),
4.25(brd,2H), 4.68(t,1H), 6.90(d,2H), 7.14(d,2H), 7.33(d,2H), 8.14(d,2H);
mass spectrunm(+ve FAB,MeOHINBA): 490(M+H)+.
EXAMPLE 99
Methyl
3-(4-methylphenylsulphonylamino)-3-4-1-(4-pyridyl)piperidin-4-yl!methoxy
phenyl!propionate
Using a procedure similar to that described in Example 33, but starting
from the product of Example 97iii) and p-tolluenesulphonyl chloride, the
title compound was prepared; NMR (CDCl.sub.3) 1.34-1.55(m,2H), 1.95(d,2H),
2.0-2.2(m,1H), 2.38(s,3H), 2.62-3.05(m,4H), 3.55(s,3H), 3.78(d,2H),
3.96(d,2H), 4.65(m,1H), 5.65(brs,1H), 6.7(d,2H), 6.72(d,2H), 7.05(d,2H),
7.2(d,2H), 7.65(d,2H), 8.25(d,2H); mass spectrum(+ve FAB,MeOH/NBA):
524(M+H).sup.+
EXAMPLE 100
Methyl
2-R-(n-butylsulphonylamino)-3-4-1-(4-pyridyl)piperidin-4-yl!methoxypheny
l!propionate
Using a procedure similar to that described in Example 33,but starting from
methyl
2-R-amino-3-4-1-(4-pyridyl)piperidin-4-yl!-methoxyphenyl!propionate,the
title compound was prepared; NMR (CDCl.sub.3) 0.88(t,3H), 1.2-1.7(m,6H),
1.96(d,2H), 2.0-2.2(m,1H), 2.7-2.83(m,2H), 2.85-3.15(m,4H), 3.77(s,3H),
3.79(d,2H), 3.96(d,2H), 4.32(m,1H), 4.85(brd,1H), 6.7(d,2H), 6.83(d,2H),
7.08(d,2H), 8.25(brd,2H); mass spectrum(+ve FAB,MeOH/NBA): 490(M+H).sup.+.
The starting material was prepared as follows:
i) Using a similar procedure to that described in Example 33i),but starting
from N-t-butyloxycarbonyl-S-tyrosine methyl ester,there was
obtained,methyl 2-R-(t-butyloxycarbonylamino)-3-4-1-(4-pyridyl)piperidin
-4-yl!methoxyphenyl!propionate as a gum,NMR (CDCl.sub.3) 1.43(s,9H),
1.36-1.55(m,2H), 1.96(brd,2H), 2.0-2.15(m,1H), 2.95(dt,2H), 3.03(d,2H),
3.71 (s,3H), 3.81 (d,2H), 3.95(brd,2H), 4.52(brd, 1H), 4.95(brd,1H),
6.70(d,2H), 6.80(d,2H), 7.01(d,2H), 8.24(d,2H).
ii) Using a similar procedure to that described in Example 95ii),but
starting from the product obtained in step i),there was obtained,methyl
2-R-amino-3-4-1-(4-pyridyl)-piperidin-4-yl!methoxyphenyl!propionate
dihydrochloride as a foam, NMR (d.sub.6 DMSO/CD.sub.3 CO.sub.2 D)
1.26-1.48(m,2H), 1.96(brd,2H), 2.1-2.3(m,1H), 3.09(dd,2H), 3.21 (t,2H),
3.70(s,3H), 3.84(d,2H), 4.15-4.3(m,3H), 6.88(d,2H), 7.14(m,4H),
8.14(d,2H).
EXAMPLE 101
2-R-(n-Butylsulphonylamino)-3-4-1-pyridyl)piperidin-4-yl!-methoxyphenyl!p
ropionic acid
Following the method of Example 34,but using the product of Example 100,the
title compound was prepared; NMR (d.sub.6 DMSO) 0.75(t,3H),
1.03-1.45(m,6H), 1.87(d,2H), 1.95-2.2(m,1H), 2.45-2.78(m,3H),
2.88-3.08(m,3H), 3.82(d,2H), 3.8-3.95(m,1H), 4.05(brd,2H), 6.84(d,2H),
6.92(d,2H), 7.18(d,2H), 8.13(brs,2H); mass spectrum(-ve FAB,MeOH/NBA):
474(M-H)- ; microanalysis found C,55.1; H,6.8; N, 7.8%; C.sub.24 H.sub.33
N.sub.3 O.sub.5 S.2.5H.sub.2 O requires C,55.4; H, 7.3; N, 8.1%.
EXAMPLE 102
cis-1-Hydroxy-44-(4-pyridyl )piperazin-1-yl !cyclohexaneacetic acid
A mixture of
cis-1,1-dimethylethyl-1-hydroxy-4-4-(4-pyridyl)piperazin-1-yl!cyclohexane
acetate (120 mg),water(0.2 ml) and trifluoroacetic acid (2 ml) was stirred
for 30 minutes at ambient temperature. The mixture was concentrated in
vacuo to give a gum which was triturated with ether to give the title
compound as a white solid; m.p. 197.degree.-200.degree. C.(dec.); NMR
(d.sub.6 DMSO/CD.sub.3 CO.sub.2 D) 1.45-1.68(m,2H), 1.8.degree.-2.0(m,6H),
2.43(s,2H), 3.15-3.34(m,1H), 3.48(brs,4H), 4.0(brs,4H), 7.23(d,2H),
8.3(d,2H); mass spectrum(+ve FAB,MeOH/NBA): 320(M+H).sup.+ ; microanalysis
found C, 45.6; H, 5.0; N, 7.2; CF.sub.3 CO.sub.2 H, 42.6%; C.sub.17
H.sub.25 N.sub.3 O.sub.3.2.1CF.sub.3 CO.sub.2 H requires C,45.6; H, 4.9;
N, 7.5; CF.sub.3 CO.sub.2 H, 42.8%.
The starting material was prepared as follows: i) Sodium cyanoborohydride
(280 mg) was added to a stirred mixture of 1,1-dimethylethyl
1-hydroxy-4-oxocyclohexane acetate (1.0 g), 1-(4-pyridyl)piperazine (830
mg),IM hydrochloric acid solution in methanol (1.5 ml) and 3A molecular
sieve (500 mg) in methanol (25 ml) at ambient temperature. The mixture was
stirred for 72 hours,filtered and the filtrate concentrated in vacuo.
Saturated sodium hydrogen carbonate solution (10 ml) and saturated sodium
chloride solution (10 ml) was added to the residue and extracted with
ethyl acetate (2.times.25 ml). The combined ethyl acetate extracts were
washed with saturated sodium chloride solution (10 ml) and
dried(MgSO.sub.4). The solvent was removed by evaporation and the residue
(1.7 g) purified by flash chromatography eluting with
methanol/dichloromethane/ triethylamine (1:9:0.2 v/v/v) to give cis-
1,1-dimethylethyl- 1-hydroxy-4-4-(4-pyridyl)piperazin-1-yl!cyclohexane
acetate as a white amorphous solid; NMR (CDCl.sub.3) 1.25-1.4(m,2H),
1.47(s,9H), 1.6-1.9(m,6H), 2.35(s,2H), 2.26-2.42(m,1H), 2.69-2.73(m,4H),
3.31-3.35(m,4H), 3.56(brs,1H), 6.65(d,2H), 8.25(d,2H).
EXAMPLE 103
Tert-butyl
1-2-4-(4-pyridyl)piperazin-1in-1-yl!acetyl!piperidin-3-yloxyacetate
A solution of t-butyl 1-(bromoacetyl)piperidin-3-yloxyacetate (1.2 g) in
acetonitrile (20 ml) was added dropwise to a stirred solution of
l-(4-pyridyl)piperazine (1.6 g) in acetonitrile (30 ml) and stirring was
continued for 1 hour. The mixture was filtered and the filtrate was
concentrated. The residue was purified by flash column chromatography,
eluting with triethylamine (1%) in ethyl acetate, to give a colourless
gum, which on crystallisation from cyclohexane, afforded the title
compound (350 mg) as colourless prisms m.p. 93.degree.-95.degree.; NMR
(d.sub.6 DMSO) .delta.1.4(9H,d); 1.3-2.0(4H,m); 2.7(4H,brs);
3.2-3.9(11H,m); 4.0(2H,d); 7.1(2H,d); 8.2(2H,d); m/e 419(M+H).sup.+ ;
calculated for C.sub.22 H.sub.34 N.sub.4 O.sub.4 : C, 63.1;H, 8.2; N,
13.4; found: C,63.4;H, 8.2; N, 13.3%.
The starting material was prepared as follows:
i) Benzylchloroformate (15 ml) was added dropwise to a stirred suspension
of 3-hydroxypiperidine hydrochloride (13,7 g) and triethylamine (30 ml) in
dichloromethane (150 ml),maintaining the temperature below 15.degree. C.
throughout. Stirring was continued for three hours,then the solution was
washed with water (4.times.100 ml) and saturated aqueous sodium chloride
(100 ml),dried (PS paper) and concentrated. The residual oil was dissolved
in ether (300 ml),washed with dilute hydrochloric acid (2.times.100 ml)
and water (100 ml),dried (PS paper) and concentrated. The residue was
purified by flash column chromatography,eluting first with hexane/ether
(1: 1) then ether to give 1-benzyloxycarbonylpiperidine-3-ol (7.1 g) as a
colourless oil. NMR (d.sub.6 DMSO) .delta.1.2-1.4(2H,m); 1.6-1.9(1 H,m +1
H,m); 2.8(1H,br s); 2.95(1 H,m); 3.45(1 H,m); 3.65(1H,brd); 3.8(1H,dd);
4.85(1H,d); 5.1(2H,s); 7.3(5H,m); m/e 236(M+H).sup.+.
ii) A solution of the product of step i) (4.7 g) in THF (100 ml) was cooled
to -30.degree. C. and treated with a solution of lithium
hexamethyldisilazide (22ml 1M in THF). The mixture was stirred for 2
minutes,cooled to -70.degree. C., treated with t-butylbromoacetate (3.5
ml) and allowed to warm to room temperature over four hours. The mixture
was diluted with ether (100 ml) and washed with water (3.times.100 ml) and
saturated aqueous sodium chloride (100 ml),dried (PS paper) and
concentrated. The residual oil was purified by flash column
chromatography, eluting with hexane/ethyl acetate (first 90: 10 then
85:15) to give t-butyl 1-benzyloxycarbonyl-piperidin-3-yloxyacetate (1.6
g) as a pale yellow oil,NMR (d.sub.6 DMSO).delta.1.4(9H,s); 1.3-1.6(2H,m),
1.65(1H,m); 1.85(1H,m); 3.25(2H,m); 3.4(2H,m); 3.6(1H,d); 4.0(2H,s);
5.0(2H,s); 7.2-7.4(5H,m); m/e 350 (M+H).sup.+.
iii) A solution of the product of step ii) (1.6 g) in isopropanol (50 ml)
was hydrogenolysed over palladium on carbon catalyst (10%, 200mg). The
mixture was filtered and the filtrate was concentrated to give t-butyl
piperidin-3-yloxyacetate as an oil which was used without further
purification.
iv) The product of step iii) was dissolved in ether (25 ml),treated with
triethlylamine (0.65 ml) and added to a stirred cooled solution of
bromoacetylbromide (0.42 ml) in ether (25 ml). Stirring was continued for
two hours and the mixture was allowed to warm to room temperature. Ether
(50 ml) was added and the solution was washed sequentially with water (50
ml), dilute aqueous sodium hydrogen carbonate (50 ml), water (50 ml) and
saturated aqueous sodium chloride (50 ml) then dried (PS paper) and
concentrated to give t-butyl (1-bromoacetyl)piperidin-3-yloxyacetate (1.2
g) as a pale brown oil which was used without further purification. NMR
(CDCl.sub.3) .delta.1.5(9H,s); 1.4-2.0(4H,m); 3.2-4.0(9H,m); m/e
336(M+H).sup.+.
EXAMPLE 104
12-4-(4-Pyridyl)piperazin-1yl!acetyl!piperidin-3-yloxyacetic acid
The product of Example 103 (340 mg) was dissolved in a mixture of
trifluoroacetic acid (10 ml) and dichloromethane (10 ml) and the solution
was allowed to stand for 1.5 hours. The solution was concentrated and the
residue was azeotroped successively with dichloromethane and ether,then
concentrated. The residual gum was passed down a Mega-bond elut column,
eluting with dichloromethane/methanol/water (5:4: 1),concentrated,
dissolved in water (25 ml) and freeze-dried to give the title compound
(250 mg) as a foam. NMR (d.sub.6 DMSO) .delta.1.2-1.8(4H,m);
3.0-4.2(15H,m); 4.35(2H,d); 7.2(2H,d); 8.2(2H,d); m/e 363(M+H).sup.+.
EXAMPLE 105
3RS, 4RS1-2-4-(4-Pyridyl)piperazin-1-yl!acetylpiperidin3,4-dioxydiacetic
acid
In a similar manner to Example 104 there was obtained the title compound as
a pale yellow solid. NMR (d.sub.6 DMSO+d.sub.4 AcOH) .delta.1.6(1H,m);
1.8(1H,m); 3.1-4.5(20H,m), 7.2(2H,d); 8.25(2H,d); m/e 437(M+H).sup.+.
The starting material was obtained using similar procedures to those
described in Example 103. The following intermediates were prepared:
1-benzyloxycarbonylpiperidine-3,4-diol. NMR (d.sub.6 DMSO)
.delta.1.2-1.4(1H,m); 1.7-1.9(1 H,m); 2.8-3.4(5H,m); 3.6-3.8(2H,m); 4.8(1
H,d); 4.9(1 H,d); 5.1 (2H,s); 7.3(5H,m); m/e 252(M+H).sup.+.
di-t-butyl 1-benzyloxycarbonylpiperidin-3,4-dioxydiacetate NMR (d.sub.6
DMSO+d.sub.4 ACOH).delta.1.4(18H,s); 1.4-1.5(l H,m); 1.9(1 H,m);
3.2-3.7(6H,m); 4.0(4H,d); 5.1(2H,s); 7.3(5H,m); m/e 480(M+H).sup.+ and
502(M+Na.sup.+).
di-t-butyl-1-bromoacetylpiperidine-3,4-dioxydiacetate m/e 466(M+H).sup.+
and 356(s) (M-2.sup.t Bu).
di-t-butyl
1-2-4-(4-pyridyl)piperazin-1-yl!acetyl-piperidin-3,4-dioxydiacetate:
used immediately without characterisation.
EXAMPLE 106
t-Butyl 12-4-(4-pyridyl)piperazin-1-yl!acetylpiperidin-4-yloxyacetate
In a similar manner to Example 103 there was obtained the title compound as
a gum. NMR (d.sub.6 DMSO).delta.1.3(9H,s); 1.3-1.5(2H,m); 1.6-1.8(2H,m);
3.0-3.3(6H,m); 3.5(3H,m); 3.6-3.9(7H,m); 3.9(2H,s); 7.05(2H,d); 8.1(2H,d).
m/e 419 (M+H).sup.+.
The starting material was obtained using similar procedures to those
described in Example 103. The following intermediates were obtained:
1-benzyloxycarbonylpiperidine-4-ol NMR (d.sub.6 DMSO).delta.1.2-1.4(2H,m);
1.6-1.8(2H,m); 3.0-3.2(2H,m); 3.6-3.8(3H,m); 4.7(1H,d); 5.1(2H,s);
7.35(5H,m). m/e 236(M+H).sup.+.
t-butyl 1-benzyloxycarbonylpiperidine-4-oxyacetate NMR (d.sub.6 DMSO)
.delta.1.3-1.5(2H,m); 1.4(9H,s); 1.7-1.9(2H,m); 3.0-3.2(2H,m);
3.5-3.6(1H,m); 3.6-3.8(2H,m); 4.0(2H,s); 5.1(2H,s); 7.3(5H,m). m/e
350(M+H).sup.+.
t-butyl 1-bromoacetylpiperidine-4-oxyacetate NMR (CDCl.sub.3)
.delta.1.45(9H,s); 1.6-2.0(4H,m); 3.4(1 H,m); 3.5(1H,m); 3.6-3.8(3H,m);
3.9(2H,s); 4.0(2H,s). m/e 336/338(M+H).sup.+ ; 358/360(M+Na)+; 280/282
(M-.sup.t Bu)+.
EXAMPLE 107
N-2-Methoxyethyl
1-2-4-(4-pyridyl)piperazin-1-yl!acetyl!-piperidin-4-yloxyacetamide
A solution of N-2-methoxyethyl 1-bromoacetylpiperidine-4-oxyacetamide (350
mg) in acetonitrile (10 ml) was added to a stirred solution of
N-(4-pyridyl)piperazine (400 mg) in acetonitrile (10 ml) and the mixture
was allowed to stand for 16 hours. The precipitate was removed by
filtration and the filtrate was concentrated. The residue was dissolved in
ethyl acetate, (15 ml) and extracted with water (3.times.10 ml). Thc
combined aqueous extracts were extracted with dichloromethane (3.times.15
ml) and the combined organic extracts were dried (PS paper) and
concentrated. The residual gum was purified by flash column chromatography
(grade II alumina) eluting first with dichloromethane and then with
methanol/dichloromethane (1:200) to give the title compound (110 mg) as a
colourless gum; NMR (d.sub.6 DMSO) .delta.1.3-1.6(2H,m); 1.6-1.9(2H,m);
3.0(4H,m); 3.05-3.25(2H,m); 3.15(3H,s); 3.25-3.4(5H,m); 3.7-3.9(7H,m);
3.9(2H,s); 7.0(2H,d); 8.1(2H,d) m/e 420 (M+H)+; m/e 442(M+Na).sup.+.
The starting material was prepared as follows:
i) A mixture of ethyl 1-benzyloxycarbonylpiperidine-4-oxyacetate (2.4 g)
and 2-methoxyethylamine (5 ml) was heated on a steam bath for 6 hours. The
amine was evaporated under reduced pressure and the residue was dissolved
in ethyl acetate (10 ml), washed sequentially with dilute citric acid
solution (5 ml), water (5 ml) and saturated aqueous sodium chloride (5
ml), dried (MgSO.sub.4) and concentrated. The residual oil was purified by
flash column chromatography,eluting with hexane/ethyl acetate (1:3) to
give N-2-methoxyethyl- 1-benzyloxycarbonylpipenidine-4-oxyacetamide (500
mg) as a colourless oil; NMR (d.sub.6 DMSO).delta.1.4-1.5(2H,m);
1.75-1.9(2H,m); 3.0-3.4(9H,m); 3.55(1 H,m); 3.65-3.8(2H,m); 3.9(2H,s);
5.1(2H,s); 7.3(5H,m); 7.6(1H,brt); m/e 351(M+H).sup.+, 373 (M+Na).sup.+.
In a similar manner to that described in Example 103, N-2-methoxyethyl
1-benzyloxycarbonylpiperidine-4-oxyacetamide was converted to
N-2-methoxyethyl -1-bromoacetylpiperidine-4-oxyacetamide; NMR
(CDCl.sub.3).delta.1.5-2.0(4H,m); 3.2-3.5(5H,m); 3.5(4H,m); 3.6-3.8(2H,m);
3.8-4.0(1H,m); 3.9(2H,s); 4.0(2H,s); 6.9(1H,brs), m/e 337/339 (M+H).sup.+
359/361(M+Na).sup.+.
EXAMPLE 108
4-2-3-4-(1-Pyrrolidinyl)pyridin-3yl!methylidene!pyrrolidin-1-yl!-acetylp
henoxyacetic acid
A solution of methyl
4-2-3-4-(1-pyrrolidinyl)pyridin-3-yl!methylidene!-pyrrolidin-1-yl!acety
l!phenoxyacetate (300 mg) in a mixture of concentrated hydrochloric acid (2
ml) and dioxan (8 ml) was heated and stirred at 50.degree. C. for 30
minutes. The solution was concentrated and the residue was dissolved in
water (20 ml),washed with ether (2.times.5 ml), treated with decolourising
charcoal, filtered and concentrated to give the title compound (161 mg) as
a pale brown foam. NMR (d.sub.6 DMSO)+d.sub.4 AcOH) .delta.2.0(4H,brs);
2.6-4.6(10H,m); 4.85(2H,s); 5.15(2H,s); 6.8(1 H,m); 6.85(1H,d); 7.1(2H,d);
8.0(2H,d); 7.9-8.1(1H,m); 8.1(1H,d); m/e 422 (M+H).sup.+.
The starting material was prepared as follows:
i) A mixture of 4-chloropyridine-3-carboxaldehyde (10 g), prepared
according to the method described in J.Het.Chem, 25,81), pyrrolidine (25
ml) and ethanol (100 ml) was heated under reflux for 5 hours, then
concentrated. The residue was purified by flash column chromatography
(grade II alumina) eluting first with dichloromethane and then with
methanol/dichloromethane (1:200) to give
3-4-(pyrrolidin-1-yl)pyridin-3-yl!methylidene!-1-pyrroline (900 mg) as a
white solid. NMR (d.sub.6 DMSO) .delta.1.8(4H,m); 2.5(2H,m); 3.3(4H,m);
3.95(2H,m); 6.6(1H,d); 7.0(1H,t), 7.9(1H,t), 8.0(1H,d); 8.15(1H,s); m/e
228(M+H).sup.+ ; calculated for C.sub.14 H.sub.17 N.sub.3 : C,74.0;H, 7.5;
N, 18.5; found C,74. 1;H, 7.7; N, 18.4%.
ii) A solution of the product of step i) (650 mg) in ethanol (20 ml) was
treated with sodium borohydride (150 mg) and the mixture was stirred for 4
hours. Glacial acetic acid (2 ml) was added and the mixture was
concentrated. The residue was treated with saturated aqueous sodium
chloride (20 ml) and saturated sodium hydrogen carbonate solution (10 ml)
and extracted with ethyl acetate (2.times.10 ml). The aqueous solution was
basified with aqueous sodium hydroxide (2.5M) and extracted with
dichloromethane (4.times.20 ml). The combined organic extracts were
concentrated to give
3-4-(pyrrolidin-1-yl)pyridin-3-yl!methylidine!pyrrolidine (350 mg) as a
yellow paste which was used without further purification. Conversion to
the hydrochloride salt using hydrogen chloride in ether/ethanol followed
by crystallisation from iso-propanol gave pale yellow prisms, m.p.
250.degree., NMR (d.sub.6 DMSO) .delta.1.95(4H,brs); 2.55(2H,m);
3.3(2H,m); 3.5-3.7(4H,brs); 3.95(2H,brs); 6.75(1H,brs); 6.85(1H,d);
8.0(1H,s); 8.15(1H,dd); 9.6-10.0(2H,brs); m/e 230(M+H).sup.+ ; calculated
for C.sub.14 HCl.sub.19 N.sub.3.2HCl. 0.1H.sub.2 O: C, 55.3; H, 7.0; N,
13.8; H.sub.2 O, 0.6; found: C,55.7; 55.5; H. 7.2, 7.1; N, 13.6; 13.5;
H.sub.2 O 0.8%.
iii) A solution of methyl 4-bromoacetyl-phenoxyacetic ester (1.2 g) in
acetonitrile (20 ml) was added dropwise to a stirred mixture of the
product of step ii) (1.0) and triethylamine (0.6 ml) in acetonitrile (20
ml),and stirring was continued for 3 hours. The mixture was concentrated
and the residue was dissolved in ethyl acetate (50 ml). The solution was
washed with water (3.times.20 ml) and saturated sodium chloride solution
(10 ml),dried (MgSO.sub.4) and concentrated to give a gum. Methanol (20
ml) was added and the solution was acidified with ethereal HCl.
Concentration gave methyl
4-2-3-(4-1-pyrrolidinyl)pyridin-3-yl!-methylidene!pyrrolidin-l-yl!-
acetyl!phenoxyacetate (650 mg) as an orange solid which was used without
further purification.
EXAMPLE 109
3-1-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!piperidin-4-yl!propanoic acid
A mixture containing ethyl
3-1-2-4-(4-pyridyl)piperazin-1-yl!acetyl!piperidin-4-yl!propanoate (50
mg), concentrated hydrochloric acid (1 ml) and dioxan (4 ml) was stirred
at 50.degree.-60.degree. C. for 1 hour,then concentrated to give a foam
which was triturated with hot isopropanol. Filtration gave the title
compound (48 mg) as pale cream prisms, m.p. 188.degree.-190.degree. C. NMR
(d.sub.6 DMSO+d.sub.4 AcOH) .delta.1.0-1.3(2H,m); 1.5-1.6(3H,m);
1.8(2H,d); 2.3(2H,t); 2.6-2.8(1H,m); 2.95-3.15(1H,m); 3.5(4H,brs);
3.6-3.7(1H,m); 4.0-4.2(4H,brs); 4.3-4.5(3H,m); 7.25(2H,d); 8.35(2H,d); m/e
361(M+H).sup.+ ; calculated for C.sub.19 H.sub.28 N.sub.4 O.sub.3 2HCl.
H.sub.2 O: C,50.6;H, 7.2; N, 12.4; H.sub.2 O, 4.0; found: C,50.3; H, 7.2;
N, 12.2; H.sub.2 O, 4.0%.
The starting material was prepared as follows:
i) Diethylazodicarboxylate (24.6 ml) was added dropwise to a stirred
solution of triphenylphosphine (39.3 g) in THF (120 ml) at 0.degree. C.
under argon. The mixture was stirred for 20 minutes,then treated
sequentially with lithium bromide (26.1 g) and a solution of
1-benzyloxycarbonylpiperidine-4-ol (7.1 g) in THF (50 ml). The mixture was
allowed to warm to room temperature and stirring was continued for 1 hour.
The mixture was concentrated, the residue treated with ether 100 (ml) and
silica (60 ml), and the solvent was evaporated under reduced pressure. The
resulting powder was added to the top of a flash column and the column was
eluted with hexane/ether (4:1) to give
1-benzyloxycarbonyl-4-bromopiperidine (3.6 g) as a colourless oil; NMR
(CDCl.sub.3) .delta.1.8-2.0(2H,m); 2.0-2.2(2H,m); 3.3-3.5(2H,m);
3.6-3.8(2H,m); 4.35(1H,m); 5.1(2H,s); 7.3(5H,m). m/e 298/300(M+H).sup.+ :
320/322(M+Na).sup.+.
ii) A solution of the product of step i) (2.6 g) in toluene (100 ml) was
stirred at 95.degree. C. under argon and treated with a solution of
tributyltin hydride (5.9 ml) in toluene (50 ml), added via a syringe pump
over 6 hours. Samples of ethyl acrylate (4.7 ml each) and
azobisisobutyronitrile (10 mg) were added at periods of Oh, 2h and 4h
during the addition of the tin hydride. The mixture was cooled,
concentrated and purified by flash column chromatography, eluting with
hexane/ethyl acetate (4:1) to give ethyl 3-(1-benzyloxycarbonyl)
piperidin-4-yl)propanoate (1.7 g). NMR (d.sub.6 DMSO)
.delta.0.9-1.1(2H,m); 1.15(3H,t); 1.3-1.5(3H,m); 1.6-1.7(2H,m); 2.3(2H,t);
2.6-2.8(2H,brt); 3.9-4.1(2H,brt+2H,q); 5.05(2H,s); 7.3(5H,m). m/e 320
(M+H).sup.+, 342(M+Na).sup.+, and ethyl
3-(1-benzyloxycarbonylpiperidin-4-yl)-2-(2-ethoxycarbonylethyl)propanoate
(0.7 g) NMR (d.sub.6 DMSO) .delta.1.2(6H, 2t); 1.0-1.8(9H,m); 2.3(2H,t);
2.45(1H,m); 2.6-2.9(2H,brt): 3.8-4.0(2H,brt); 4.0-4.2(4H, 2q); 5.05(2H,s);
7.3(5H,m); m/e 420(M+H)+,442(M+Na).sup.+.
iii) In a similar manner to that described in Example 103,ethyl
3-(1-benzyloxycarbonylpiperidin-4-yl)propanoate was converted to ethyl
3-1-2-4-(4-pyridyl)piperazin- 1-yl!acetyl!piperidin-4-yl!propanoate.
The following intermediates were isolated:
ethyl-1-bromoacetylpiperidin-4-ylpropanoate. NMR (CDCl.sub.3)
.delta.1.1-1.4(2H,m); 1.25(3H,t); 1.5-1.7(3H,m); 1.7-1.9(2H,t); 2.3(2H,t);
2.5-2.7(1 H,td); 3.0-3.2(1H,td); 3.8-4.0(2H,d)+1 H,m); 4.15(2H,q);
4.55(1H,m); m/c 306/308(M+H).sup.+, ethyl 3-1-
2-4-(4-pyridyl)piperazin- 1-yl!acetyl!piperidin-4-yl!propanoate. m.p.
90.degree.-92.degree. C.; NMR (d.sub.6 DMSO) .delta.0.85-1.0(1 H,m);
1.05-1.2(1H,m); 1.2(3H,t); 1.5(3H,m); 1.7(2H,m); 2.3(2H,t); 2.5(4H,brs);
2.8-3.0(1 H,t); 3.1(1H,d); 4.05(2H,q+1 H,m); 4.3(1 H,d); 6.8(2H,d);
8.15(2H,d); m/e 389 (M+H).sup.+ 411 (M+Na)+; calculated for C.sub.21
H.sub.32 N.sub.4 O.sub.3 ; C, 64.9; H, 8.3; N, 14.4; found: C, 65.0; H,
8.5; N, 14.4%.
EXAMPLE 110
Ethyl
2RS-(n-butylsulphonylamino)-3-1-2-4-(4-pyridyl)piperazin-1yl!-acetyl!pi
peridin-4-yl!propanoate
A mixture containing ethyl
(2-n-butylsulphonylamino)-3-1-(2-bromoacetyl)piperidin-4-yl!propanoate
(330 mg), 1-(4-pyridyl)piperazine (150 mg), triethylamine (0.13 ml) and
acetonitrile (20 ml) was stirred for 16 hours. The mixture was
concentrated and the residue was dissolved in ethyl acetate (50 ml). The
solution was washed with water (2.times.20 ml) and saturated aqueous
sodium chloride (20 ml),dried (MgSO.sub.4) and concentrated. The residue
was dissolved in ethanol (20 ml), treated with decolourising charcoal,
filtered and concentrated to give the title compound (136 mg) as a
colourless glass. NMR (d.sub.6 DMSO+d.sub.4 AcOH) .delta.0.8(3H,t); 1.0(1
H,m); 1.1(3H,t); 1.3(2H,m); 1.5-1.8(8H,m); 2.9(4H,m); 3.2(4H,brs); 3.65(1
H,m); 3.8-4.1(4H,brs+3H,m+2H,q); 4.35(1H,m); 7.1(2H,d); 8.1 (2H,d); m/e
524(M+H).sup.+.
The starting material was prepared as follows:
i) A solution of methanesulphonylchloride (7.7 ml) in dichloromethane (50
ml) was added dropwise to a stirred solution of
1-benzyloxycarbonyl-4-hydroxymethylpiperidine (23.4 g) in dichloromethane
(350 ml) cooled to 5.degree. C. Stirring was continued for 1 hour, then
the solution was washed with water (4.times.150 ml) and saturated aqueous
sodium chloride (100 ml), dried and concentrated. The residue was
crystallised from tetrachloromethane (250 ml) to give
1-benzyloxycarbonyl-4-methanesulphonyloxymethylpiperidine (20 g) as
colourless prisms, m.p. 72.degree.-74.degree. C. NMR (CDCl.sub.3)
.delta.1.1-1.4(2H,m); 1.7-1.8(2H,d); 1.9-2.1(1H,m); 2.7-2.9(2H,t);
3.0(3H,s); 4.05(2H,d); 4.1-4.4(2H,d); 5.1(2H,s); 7.3(5H,m); m/e
328(M+H)+350 (M+Na).sup.+ ; calculated for C.sub.15 H.sub.21 N.sub.5
O.sub.5 : C, 55.0;H, 6.5; N, 4.3; found: C, 54.8; H, 6.6; N, 4.2%.
ii) A mixture containing triethylbenzylammonium bromide (0.3 g), the
product of step i) (3.27 g),ethyl N-diphenylmethylidene glycine ester (3.0
g), potassium carbonate (4.2 g) and acetonitrile (45 ml) was heated under
reflux for 48 hours, concentrated, and the residue was partitioned between
ethyl acetate (100 ml ) and water (100 ml). The ethyl acetate fraction was
washed with water (2.times.50 ml) and saturated aqueous sodium chloride
(50 ml), dried (MgSO.sub.4) and concentrated. The residue was purified by
flash column chromatography, eluting with hexane/ether (3: 1) to give
ethyl 2RS-(diphenylmethylidene amino)-3-(l-benzyloxy-
carbonylpiperidin-4-yl)propanoate (650 mg) as a pale yellow oil. NMR
(d.sub.6 DMSO) .delta.0.8-1.6(5H,m); 1.2(3H,t); 1.8(2H,t); 2.6-2.8(2H,m);
3.8-4.0(3H,m); 4.1(2H,q); 5.05(2H,s); 7.1-7.6(15H,m); m/e 499(M+H).sup.+ ;
42 1 (M+Na).sup.+.
iii) A mixture of the product of step ii) (1.1 g), saturated hydrogen
chloride in ether solution (15 ml) and ethanol (50 ml) was allowed to
stand for 1 hour. The solution was concentrated and the residue was
stirred with ether (30 ml) to give a colourless solid. The solid was
filtered off, washed with ether (30 ml) and dried to give ethyl
2RS-amino-3-(1-benzyloxycarbonylpiperidin-4-yl)propanoate hydrochloride
(700 mg) as a colourless solid which was used without further
purification. A sample (50 mg) was recrystallised from ethyl acetate (10
ml) to give colourless prisms (30 mg), m.p. 122.degree.. NMR (d.sub.6
DMSO) .delta.0.9-1.1 (2H,br.m); 1.25(3H,t); 1.6-1.8(5H,br.m);
2.6-2.9(2H,br.m); 3.9-4.1(3H,br.m); 4.2(2H,dq); 5.1(2H,s); 7.3(5H,m);
8.4-8.7(3H,br.s); m/e 335(M+H).sup.+ ; calculated for C.sub.18 H.sub.26
N.sub.2 O.sub.4.HCl: C, 58.3; H, 7.3; N, 7.6; found: C, 58.2;H, 7.7; N,
7.5%.
iv) A mixture of the product of step iii) (650 mg),
n-bitylsulphonylchloride (0.25 ml), triethylamine (0.55 ml) and
dichloromethane (30 ml) was stirred for 4 hours at room temperature, then
diluted with dichloromethane (50 ml), washed with water (3.times.50 ml)
and saturated aqueous sodium chloride (50 ml), dried (PS paper) and
concentrated. The residue was purified by flash column chromatography,
eluting with hexane/ethyl acetate (3: 1) to give ethyl
2RS-(n-butylsulphonylamino)-3-(1-benzyloxycarbonylpiperidin-4-yl)propanoat
e (400 mg) as a colourless gum. NMR (d.sub.6 DMSO) .delta.0.9(3H,t);
1.0-1.2(2H,m); 1.25(3H,t); 1.3-1.5(2H,m); 1.5-1.8(7H,m); 2.6-2.9(2H,m);
2.8-3.1 (2H1,m); 3.8-4.1(3H,m); 4.1 5(2H,q); 5.1(2H,s); 7.3(5H,m);
7.7(1H,d); m/e 455 (M+H).sup.+ ; 477(M+Na).sup.+.
In a similar manner to that described in Example 103,the carbonyl-protected
piperidine was converted to the N-bromoacetyl analogue, which was isolated
as a colourless gum and used without further purification.
EXAMPLE 111
2-RS-(n-Butylsulphonylamino)-3-1-2-4-(4-pyridyl)-piperazin-1-yl!acetyl!p
ropanoic acid
A mixture of the product of Example 110 (50 mg), concentrated hydrochloric
acid (1 ml) and dioxan (4 ml) was stirred at 50.degree. C. for one hour,
then concentrated, triturated with acetone and dried under vacuum. The
residual solid was stirred with dioxan (3 ml) and concentrated
hydrochloric acid (2 ml) at 70.degree. C. for 1 hour then concentrated and
dried under vacuum to give the title compound (34.3 mg) as a pale yellow
solid. NMR (d.sub.6 DMSO +d.sub.4 AcOH) .delta.0.8 (3H,t); 1.0-1.2(1H,m);
1.3(2H,m); 1.5-1.8(8H,m); 2.8-3.0(4H,m); 3.4-3.6(6H,m); 4.0(4H,brs);
4.1-4.4(3H,m); 7. 1(2H,d); 8.1(2H,d); m/e 496 (M+H).sup.+ ; 518
(M+Na).sup.+.
EXAMPLE 112
3-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!piperidin-4-yl!-3-
2-(2-carboxyethyl)!propanoic acid
A mixture containing ethyl
3-1-2-4-(4-pyridyl)piperazin-1-yl!acetyl!piperidin-4-yl!-3-2-(2-ethoxy
carbonylethyl)!- propanoate, concentrated hydrochloric acid (2 ml) and
dioxan (3 ml) was stirred at 70.degree. C. for 1 hour, concentrated and
dried under vacuum. The residue was triturated with acetone and redried to
give the title compound (52 mg) as a pale yellow foam. NMR (d.sub.6 DMSO
+d.sub.4 AcOH) .delta.0.9-1.1 (1 H,m); 1.2-1.3(1 H,m); 1.5(3H,m); 1.7(2H,t
+2H,m); 2.2(2H,t); 2.35(1 H,m); 2.6(1 H,m); 2.7-3.0(2H,m); 3.2(1 H,m);
3.5(4H,m); 4.0(4H,m); 4.8(2H,d); 7.1(2H,d); 8.2(2H,d); m/e 433(M+H).sup.+.
The starting material was prepared as a pale yellow gum from ethyl
3-(1-benzyloxycarbonylpiperidin-4-yl)-2-(2-ethoxycarbonylethyl)propanoate
using a similar procedure to that described for the monoester in Example
109.
EXAMPLE 113
4-4-(4-Dimethylaminopyrid-3-yl)methoxy!phenoxy!butanoic acid
A mixture containing ethyl
4-14-(4-dimethylaminopyrid-3-yl)methoxy!phenoxy!-butanoate (25 mg),
aqueous sodium hydroxide (1M, 0.2 ml), methanol (0.5 ml) and water (0.5
ml) was stirred for 3 hours then neutralised with hydrochloric acid (1M,
0.2 ml) and concentrated. The residue was dissolved in dichloromethane (5
ml), filtered, and the filtrate was concentrated to give the title
compound (17 mg) as a colourless gum. NMR (d.sub.6 DMSO +d.sub.4 AcOH)
.delta.2.0(2H,q); 2.4(2H,t); 3.35(6H,s); 3.95(2H,t); 5.1(2H,s);
6.8-7.0(4H,dd +1 H,m); 8.15(1 H,dd); 8.3(1 H,d); m/e 331 (M+H).sup.+.
The starting material was prepared as follows:
i) A solution of 4-dimethylaminopyridine-3-carboxaldehyde (J. Het. Chem,
25, 81) (1.5 g) in ethanol (25 ml) was treated with sodium borohydride
(200 mg) and the mixture was stirred for 4 hours. Concentrated
hydrochloric acid (1 ml) was added and the mixture was concentrated. The
residue was treated with saturated aqueous sodium chloride (40m) and
concentrated aqueous sodium hydroxide (2 ml) and the mixture was extracted
with dichloromethane (4.times.20 ml). The combined organic extracts were
washed with saturated aqueous sodium chloride (40 ml), dried (PS paper)
and concentrated. The residue was dissolved in methanol, treated with
decolourising charcoal, filtered and concentrated to give
4-dimethylaminopyridine-3-methanol (1.1 g) as a pale yellow oil. NMR
(d.sub.6 DMSO) .delta.2.9 (6H,s); 4.5(2H,s); 4.0-4.8(1H,br.s); 6.7(1H,d);
8.15(1H,d); 8.3(1H,s); m/e 153 (M+H).sup.+ ; 135(M+H-H.sub.2 O).sup.+.
ii) A mixture containing the product of step i) (300 mg), ethyl
4-(4-hydroxyphenoxy)butanoate (450 mg), triphenylphosphine (0.58 g) and
dichlorometlhane (5 ml) was stirred for 30 minutes then treated dropwise
with diethylazodicarboxylate (0.35 ml). The mixture was stirred for 2
hours then diluted with ether (50 ml), washed with water (2.times.25 ml)
and saturated aqueous sodium chloride (25 ml), dried (MgSO.sub.4) and
concentrated. The residue was purified by flash column chromatography
eluting with ethanol/dichloromethane (3:97) to give ethyl
4-14-(4-dimethylamilopyrid-3-yl)methoxylphenoxybutanoate (200 mg) as a
colourless solid. NMR (d.sub.6 DMSO +d.sub.4 AcOH) .delta.1.1(3H,t);
1.9(2H,q); 2.3(2H,t); 3.2(6H,s); 3.8(2H,t); 3.95(2H,q); 5.0(2H,s);
6.7-6.9(2H,d +1H,d +2H,d); 8.0(1H,dd); 8.15(1H,d); m/e 359 (M+H).sup.+.
EXAMPLE 114
Methyl3-(4-dimethylamninopyrid-3-yl)methoxyphenoxyl-2-benzyloxycarbonylamin
opropanoate
A stirred mixture containing 4-dimethylaminopyridine-3-methanol (700 mg),
triphenylphosphine (1.3 g), N-benzyloxycarbonyltyrosine methyl ester (1.66
g) and THF (50 ml) was treated dropwise with diethylazodicarboxylate (1.3
g) and the mixture was stirred for 4.5 hours and concentrated. The residue
was purified by flash column chromatography eluting with
methanol/dichloromethane (first 1:99, then 2:98) to give the title
compound (900 mg) as a colourless foam. NMR (d.sub.6 DMSO)
.delta.2.7-3.1(2H,m); 2.9(6H,s); 3.6(3H,s); 4.2(1 H,m); 4.95(2H,s);
5.05(2H,s); 6.8(1H,d); 6.9(2H,d); 7.15(2H,d); 7.2-7.4(5H,m); 7.75)1H,d);
8.3(1 H,s); m/e 464(M+H).sup.+.
EXAMPLE 115
N-1-2-4-(4-Pyridiyl)piperazin-1-yl!acetyl!piperidin-4-ylmethyl!-1-butane
sulphonamide
A mixture containing 4-n-butylsulphonylaminomethyl-N-bromoacetylpipelidine
(250 mg),1-(4-pyridyl)piperazine (125 mg),triethylamine (0.11 ml) and
acetonitrile (10 ml) was stirred for 16 h and concentrated. The residue
was purified by flash column chromatography, eluting with
dichloromethanolmethanol/triethylamine (95:5:0.5), to give a colourless
solid (280 mg). The solid was dissolved in water (5 ml) and extracted with
ethyl acetate (3.times.5 ml). The combined organic extracts were washed
with saturated aqueous sodium chloride (5 ml), dried (MgSO.sub.4) and
concentrated to give the title compound (90 mg) as a colourless oil. NMR
(d.sub.6 DMSO +d.sub.4 AcOH) .delta.0.8(3H,t); 1.4(2H,m); 0.9-1.8(2H,m
+2H,m +2H,m +1 H,m); 2.6(1H,t); 2.7-3.0(2H,d +2H,m +1H,t); 3.3(4H,brs);
3.6(1H,brd); 3.9(4H,brs); 3.9-4.2(2H,dd); 4.3(1H,brd), 7.1(2H,d);
8.15(2H,d); m/e 438(M+H).sup.+.
The starting material was prepared as follows:
i) A solution of n-butylsulphonamide (500 mg) in DMF (5 ml) was added
dropwise to a suspension of sodium hydride (150 mg, 60% dispersion in
mineral oil) in DMF (10 ml) and the mixture was stirred for 10 minutes.
4-Methanesulphonyloxymethyl-N-benzyloxy-carbonylpiperidine (1.09 g) was
added and the mixture heated at 80.degree. C. for 16 hours. The mixture
was cooled, poured into water (100 ml) and extracted with ethyl acetate
(3.times.50 ml). The combined organic extracts were washed with water
(3.times.50 ml) and saturated aqueous sodium chloride (50 ml), dried
(MgSO.sub.4) and concentrated. The residual oil was purified by flash
column chromatography, eluting with methanol/dichloromethane (1:99) to
give a colourless semi-solid. This mixture was dissolved in warm
tetrachloromethane (6 ml) and cooled to give
4-n-butylsulphonylaminomethyl-N-benzyloxycarbonylpiperidine (230 mg) as
colourless prisms, mp 83.degree.-85.degree. C. NMR (d.sub.6 DMSO)
.delta.0.9(3H,t), 0.9-1.1(2H,m); 1.3-1.5(2H,m); 1.5-1.8(5H,m);
2.7-2.9(4H,m); 2.95(2H,m); 4.0(2H,d); 5.1(2H,s); 7.0(1H,t); 7.3(5H,m). m/e
369(M+H).sup.+ ; 391(M+Na).sup.+ ; calculated for C.sub.18 H.sub.28
N.sub.2 SO.sub.4 : C, 58.7; H, 7.7; N, 7.6; found: C, 58.5; H, 7.8; N,
7.6%.
The N-benzyloxycarbonyl-protected piperidine was converted to the
N-bromoacetyl analogue using a similar procedure to that described in
Example 103. The N-bromoacetyl compound was used immediately in the
preparation of product.
EXAMPLE 116
Methyl 4-2-4-(4-pyridyl)piperazin-1-yl!-2,6-dichlorophenoxyacetate
Prepared in a similar manner to Example 5,but starting from methyl
4-bromoacetyl-2,6-dichlorophenoxyacetate, however stirring for only 6
hours and purification by flash chromatography on silica, eluting first
with dichloromethane then successively 2,3,4 and 5% v/v
methanol/dichloromethane. Concentration of the fractions in vacuo and
recrystallisation of the residue from methanol gave the title compound in
24% yield as a pale orange solid: m.p. 149.degree.-150.degree. C.; NMR
(d.sub.6 DMSO) .delta.8.14(2H,d), 8.06(2H,s), 6.81(2H,d), 4.82(2H,s),
4.05(0.5H,b), 3.94(2H,s), 3.73(3H,s), 3.32(4H,t), 3.18(1.5H,s),
2.64(4H,t); m/e 438 (M+H).sup.+, 3207 2.times.Cl pattern; calculated for
C.sub.20 H.sub.21 Cl.sub.2 N.sub.3 O.sub.4.0.5CH.sub.3 OH: C, 54.1; H,
5.1; N, 9.2. found: C, 53.7; H, 5.4; N, 8.9%.
The starting material was prepared as follows:
i) Sodium hydride (50% w/w dispersion in mineral oil, 1.32 g) was treated
under argon with repeated washes of hexane. The oil-free residue was
suspended in dry DMF (10 ml) and, with stirring and cooling (ice-bath), a
solution of 3,5-dichloro-4-hydroxyacetophenone (5.13 g) in dry DMF (15 ml)
was added dropwise. Stirring was continued for 30 minutes when methyl
bromoacetate (3.06 ml) was added dropwise and stirring was continued for a
further 18 hours at ambient temperature. The reaction mixture was added to
water, the mixture was extracted twice with ethyl acetate, the organic
phases dried (MgSO.sub.4), filtered and then evaporated. The residue,
after recrystallisation from hexane (250 ml), gave methyl
4-acetyl-2,6-dichlorophenoxyacetate, 4.25 g, as white crystals: NMR
(d.sub.6 DMSO) .delta.8.00(2H,s), 4.80(2H,s), 3.73(3H,s), 2.59(3H,s).
ii) A solution of bromine (0.77 ml) in chloroform (10 ml) was added
dropwise over 15 minutes to a stirred solution of the product from step i)
(4.16 g) in chloroform (40 ml) at 25.degree. C. The temperature was raised
to 40.degree. C. for 1 hour and then stirring continued for a further 18
hours at ambient temperature. The solvent was removed in vacuo and the
residual oil purified by flash chromatography on silica, eluting with
dichloromethane, to give a crystalline solid. Recrystallisation from
methanol gave methyl 4-bromoacetyl-2,6- dichlorophenoxyacetate, 1.88 g, as
white crystals: m.p. 89.degree.-90.degree. C.; NMR (d.sub.6 DMSO) .delta.
8.06(2H,s), 4.93(2H,s), 4.82(2H,s), 3.72(3H,s); m/e 355/357 (M+H).sup.+, 1
Br pattern; calculated for C.sub.11 H.sub.9 BrCl.sub.2 O.sub.4 : C, 37.1;
H, 2.3. found: C, 36.8; H, 2.4%.
EXAMPLE 117
Methyl4-2-4-(4-pyridyl)piperazin-1-acetyl!-1-naphthoxyacetate
Prepared in a similar manner to Example 5,but starting from methyl
4-bromoacetylnaphthoxyacetate and purification by flash chromatography on
silica, eluting with dichloromethane then increasing concentrations of
methanol to 5% v/v methanol/dichloromethane. Trituration with ether gave
the title compound in 13% yield, as a solid: m.p. 140.degree.-142.degree.
C.; NMR (d.sub.6 DMSO) .delta. 8.70(1H,dd), 8.32(1H,dd), 8.23(1H,d),
8.16(2H,bd), 7.64(2H,m), 7.00(1H,d), 6.80(2H,d), 5.14(2H,s), 3.92(2H,s),
3.75(3H,s), 3.31(4H,t), 2.67(4H,t); m/e 420 (M+H).sup.+ ; calculated for
C.sub.24 H.sub.25 N.sub.3 O.sub.4.0.25 H.sub.2 O: C, 67.9; H, 6.0; N, 9.9.
found: C, 67.8; H, 6.0; N, 9.7%.
The starting material was prepared as follows:
i) In a similar manner to Example 116i), but starting from
4-acetyl-1-naphthol, there was obtained methyl 4-acetyl-
1-naphthoxyacetate in 62% yield as a white crystalline solid: m.p.
123.degree.-125.degree. C.; NMR (d.sub.6 DMSO) .delta. 8.89(1H,dd),
8.31(1H,dd), 8.19(1H,d), 7.63(2H,m), 7.00(1 H,d), 5.14(2H,s), 3.76(3H,s),
2.68(3H,s); m/e 259 (M+H).sup.+ ; calculated for C.sub.15 H.sub.14 O.sub.4
: C, 69.8; H, 5.5. found: C, 69.7; H, 5.4%.
ii) A mixture of the product from step i) above (2.0 g) and cupric bromide
(3.45 g) in ethyl acetate (35 ml) was heated at reflux temperature for 24
hours. On cooling, the mixture was filtered,concentrated in vacuo and the
residue purified by flash chromatography on silica eluting with
dichloromethane. Evaporation of the fractions gave methyl
4-bromoacetyl-1-naphthoxyacetate as a white solid: m.p.
99.degree.-101.degree. C.; NMR (d.sub.6 DMSO) .delta. 8.73(l H,d),
8.34(1H,d), 8.26(1H,d), 7.59 to 7.82(2H,m), 7.02(1H,d), 5.15(2H,s),
4.97(2H,s), 3.76(3H,s); m/e 337/339 (M+H).sup.+, 1 Br pattern.
EXAMPLE 118
Methyl 4-2-4-(4-pyridyl)piperazin-1-yl!acetyl!-3-methylphenoxyacetate
In a similar manner to Example 5,but starting from methyl
4-bromoacetyl-3-methylphenoxyacetate and with purification by flash
chromatography on silica, eluting with 0 to 5% v/v
methanol/dichloromethane,and then by flash chromatography on neutral
alumina, eluting first with dichloromethane and then 1% v/v
methanol/dichloromethane there was obtained the title compound in 9% yield
as a yellow oil: NMR (d.sub.6 DMSO) .delta. 8.15(2H,d), 7.38(1H,d),
6.82(4H,m), 4.88(2H,s), 3.75(2H,s), 3.71(3H,s), 3.32(4H,t), 2.61(4H,t),
2.43(3H,s), m/e 384 (M+H).sup.+ ; calculated for C.sub.21 H.sub.25 N.sub.3
O.sub.4.0.5H.sub.2 O.0.1CH.sub.2 Cl.sub.2 : C, 63.1; H, 6.5; N, 10.5.
found: C, 62.6; H, 6.6; N, 10.2%.
The starting material was prepared as follows:
i) A mixture of 4-hydroxy-2-methylacetophenone (4.8 g), anhydrous potassium
carbonate (5.3 g) and methyl bromoacetate (3.55 ml) in anhydrous acetone
(100 ml) was stirred for 2 days. The mixture, after filtration and
evaporation of the solvent, gave methyl 4-acetyl-3-methylphenoxyacetate,
6.6 g, as a crystalline solid: m.p. 49.degree.-50.degree. C.; NMR (d.sub.6
DMSO) .delta. 7.84(1H,d), 6.83(2H,m), 4.87(2H,s), 3.71(3H,s), 2.50(3H,s),
2.45(3H,s).
ii) Prepared in a similar manner to Example 117ii), but starting from the
product of i) above and purification by flash chromatography on silica
eluting with 10 to 17.5% v/v ethyl acetate/hexane. Recrystallisation from
ethanol gave methyl 4-bromoacetyl-3-methylphenoxyacetate, in 35% yield, as
white needles: NMR (d.sub.6 DMSO) .delta. 7.90(1H,d), 6.90(1H,s),
6.88(1H,d), 4.90(2H,s), 4.78(2H,s), 3.71(3H,s), 2.43(3H,s).
EXAMPLE 119
Methyl 3-2-4-(4-pyridyl)piperazin-1-yl!phenoxyacetate
Prepared in a similar manner to Example 5,but starting from methyl
3-bromoacetylphenoxyacetate and with purification by flash chromatography
on silica, eluting with 10% v/v methanol/dichloromethane. Trituration with
ether gave the title compound in 20% yield: m.p. 114.degree.-116.degree.
C.; NMR (d.sub.6 DMSO) .delta. 8.15(2H,b), 7.61(1H,dd), 7.50(1H,m),
7.43(1H,t), 7.21(1H,dd), 6.83(2H,d), 4.87(2H,s), 3.91(2H,s), 3.70(3H,s),
3.35(4H,t), 2.64(4H,t); m/e 370 (M+H).sup.+ ; calculated for C.sub.20
H.sub.23 N.sub.3 O.sub.4.0.5H.sub.2 O: C, 63.5; H, 6.4; N, 11.1. found: C,
63.5; H, 6.5; N, 10.6%.
The starting material was prepared as follows:
i) In a similar manner to Example 116ii), but starting from the methyl
3-acetylphenoxyacetate and purification by flash chromatography on silica,
eluting with ethyl acetate/hexane (1:1 v/v) there was obtained methyl
3-bromoacetylphenoxyacetate in 64% yield as a pale fawn solid: NMR
(CDCl.sub.3) .gamma. 7.61(1H,d), 7.50(1H,m), 7.43(1H,t), 7.20(1H,dm),
4.70(2H,s), 4.44(2H,s), 3.82(3H,s); m/e 287/289 (M+H).sup.+, 1 Br pattern.
EXAMPLE 120
Mixture of methyl
4-2-4-(4-pyridyl)piperazin-1-yl!acetyl!-2-methylphenoxyacetate and ethyl
4-2-4(4-pyridyl)piperazin-1-yl!acetyl!-2-methylphenoxyacetate (3:2)
A mixture of methyl 4-acetyl-2-methylphenoxyacetate (3.33 g) and cupric
bromide (7.0 g) in ethyl acetate (50 ml) was heated on a steam bath for 18
hours. After filtration, the solvent was evaporated and the residual solid
purified by flash chromatography on silica eluting with 10% v/v ethyl
acetate/hexane to give an off-white solid. Recrystallisation from ethanol
save white needles, 2.37 g, shown by NMR (d.sub.6 DMSO) to be a mixture of
methyl 4-bromoacetyl-2-methylphenoxy- acetate and ethyl
4-bromoacetyl-2-methylphenoxyacetate which was used without further
purification. The mixture (2.25 g) was added portionwise to a stirred
solution of 1-(4-pyridyl)piperazine (2.45 g) in acetonitrile (50 ml) and
the mixture stirred for 18 hours. The reaction mixture was filtered and
the filtrate evaporated to give an orange oil. Purification by flash
chromatography on silica eluting with dichloromethane then 1 to 3% v/v
methanol/dichloromethane gave the title mixture of compounds, 0.87 g, as a
solid: m.p. 136.degree.-138.degree. C.; NMR (d.sub.6 DMSO) .delta.
8.04(2H,d), 7.85(1H,d), 7.82(1H,s), 6.95(1H,d), 6.81(2H,d), 4.96 and
4.93(2H,s,s), 4.18(0.7H,q), 3.84(2H,s), 3.72(1.7H,s), 3.30(4H,t),
2.60(4H,t), 2.25(3H,s), 1.21(1.3H,t), Ratio of methyl to ethyl ester
3:2!; m/e 384 (M+H).sup.+ for methyl ester, 398 (M+H).sup.+ for ethyl
ester; calculated for C.sub.21 H.sub.25 N.sub.3 O.sub.4 : C.sub.22
H.sub.27 N.sub.3 O.sub.4 (3:2): C, 66. 1;H, 6.6; N, 10.8. found: C, 65.8;
H, 6.7; N, 10.5%.
The starting material was prepared as follows:
i) A mixture of 4-hydroxy-3-methylacetophenone (5 g), methyl bromoacetate
(3.70(ml) and anhydrous potassium carbonate (5.52 g) in acetone (100 ml)
was stirred for 66 hours. The mixture was filtered and the filtrate
evaporated to give an oil which crystallised on standing to give methyl
4-acetyl-2-methylphenoxyacetate, 7.2 g: m.p. 51.degree.-53.degree. C.; NMR
(d.sub.6 DMSO) .delta. 7.79(1H,s), 7.77(1H,d), 6.94(1H,d), 4.93(2H,s),
3.71(3H,s), 2.50(3H,s +DMSO), 2.24 (3H,s).
EXAMPLE 121
Mixture of methyl
4-2-4-(4-pyridyl)piperazin-1-yl!acetyl!-3-methoxyphenoxyacetate and
ethyl4-2-4-(4-pyridyl)piperazin-1-yl!acetyl!-3-methoxyphenoxyacetate
(3:1)
In a similar manner to Example 120,but starting from methyl
4-acetyl-3-methoxyphenoxyacetate there was prepared, after flash
chromatography on silica eluting with dichloromethane, a mixture of methyl
4-bromoacetyl-3-methoxyphenoxyacetate and ethyl 4-bromoacetyl-3-
methoxyphenoxyacetate in 60% yield: m.p. 84.degree.-86.degree. C.
Treatment of this mixture, as in Example 120, followed by chromatography
on silica eluting with 1 to 5% v/v methanol/dichloromethane gave the title
mixture of compounds in 24% yield as a solid: NMR (d.sub.6 DMSO) .delta.
8.13(2H,d), 7.63(1H,d), 6.80(2H,d), 6.67(1H,d), 6.59(1H,dd), 4.90 and
4.88(2H,2s), 4.18(0.5,q), 3.88(3H,s), 3.75(2H,s), 3.71(2.3H,s),
3.32(4H,t), 2.62(4H,t), 1.22(0.7H,t) Ratio of methyl to ethyl ester 3:1!;
m/e 400 (M+H).sup.+ for methyl ester, 414 (M+H).sup.+ for ethyl ester;
calculated for C.sub.21 H.sub.25 N.sub.3 O.sub.5 : C.sub.22 H.sub.27
N.sub.3 O.sub.5 (3: 1): C, 63.3;H, 6.5; N, 10.4. found C, 63.1; H, 6.5, N,
10.3%.
The starting material was prepared as follows:
i) In a similar manner to Example 120i), but starting from
4-hydroxy-2-methoxy-acetophenone there was obtained, after evaporation of
the solvent and trituration with diethyl ether, methyl
4-acetyl-3-methoxyphenoxyacetate in 91% yield as a white solid: m.p.
95.degree.-96.degree. C.; NMR (d.sub.6 DMSO) .delta. 7.64(1H,d),
6.70(1H,d), 6.60(1H,dd), 4.91(2H,s), 3.89(3H,s), 3.72(3H,s), 2.49(3H,s).
EXAMPLE 122
Mixture of dimethyl
2,2'-4-2-4-(4-pyridyl)piperazin-1-yl!acetyl!-phenylene-1,3-dioxy!diacet
ate and diethyl
2,2'-4-2-4-(4-pyridyl)piperazin-1-yl!acetyl!phenylene-1,3-dioxy!-
diacetate(1:1)
In a similar manner to Example 120, but starting from dimethyl
2,2'-(4-acetyl)phenylene-1,3-dioxy!diacetate there was prepared, after
flash chromatography on silica eluting with dichloromethane, a mixture of
dimethyl 2,2'-(4-bromoacetyl)phenylene-1,3-dioxy!diacetate and diethyl
2,2'-(4-bromoacetyl)phenylene-1,3-dioxy!diacetate in 28% yield. Treatment
of the mixture,as in Example 120, followed by chromatography on silica
eluting with 1 to 5% v/v methanol/dichloromethane gave the title mixture
of compounds in 44% yield as a solid: NMR (d.sub.6 DMSO) .delta.
8.14(2H,d), 7.63(1H,d), 6.82(2H,d), 6.65(2H,d), 4.96+4.93(2H,2s), 4.49 and
4.47(2H,2s), 4.20(2H,m), 3.91(2H,s), 3.75 and 3.71(3H, 2s), 3.32(4H
+H.sub.2 O), 2.61(4H,t), 1.23(3H,m) Ratio of methyl to ethyl esters 1:1!;
m/e 458 (M+H).sup.+ for dimethyl ester and 486 (M+H).sup.+ for diethyl
ester; calculated for C.sub.23 H.sub.27 N.sub.3 O.sub.7 : C.sub.25
H.sub.31 N.sub.3 O.sub.7 (1:1). H.sub.2 O: C, 60.0;H, 6.3; N, 8.7. found:
C, 60.3;H, 6.2; N, 8.5%.
The starting material was prepared as follows:
i) In a similar manner to Example 120i),but starting from
2,4-dihydroxy-acetophenone and using 2.4 equivalents of methyl
bromoacetate and 2.4 equivalents of anhydrous potassium carbonate there
was obtained, after evaporation and trituration with diethyl etherhexane
(1:1 v/v), dimethyl 2,2'-(4-acetyl)phenylene-1,3-dioxyldiacetate in 82%
yield as a white solid: m.p. 119.degree.-120.degree. C.; NMR (d.sub.6
DMSO) .delta. 7.64(1H,d), 6.56(2H,m), 4.99(2H,s), 4.90(2H,s), 3.73(3H,s),
3.71(3H,s), 2.57(3H,s).
EXAMPLE 123
4-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!-2,6-dichlorophenoxyacetic acid,
dihydrochloride
A solution of the product Example 116 (190 mg) in dioxane (1.7 ml) was
treated with 1N hydrochloric acid (1.7 ml) and the mixture heated at
100.degree. C. for 1.5 hours. The mixture was cooled, diluted with water
and freeze-dried. The solid residue,on treatment with a small volume of
ethanol, gave the title compound, 120 mg, as a white solid: m.p.
174.degree.-176.degree. C.; NMR (D.sub.2 O) .delta. 8.42(2H,d),
8.26(2H,s), 7.41(2H,d), 5.24(2H,s), 4.98(2H,s), 4.34(4H,t), 3.90(4H,t);
m/e 424 (M+H).sup.+, 2.times.Cl pattern; calculated for C.sub.19 H.sub.19
Cl.sub.2 N.sub.3 O.sub.4.2HCl.H.sub.2 O: C, 44.4;H, 4.5; N, 8.2. found: C,
44.8; H, 4.2; N, 8.1%.
EXAMPLES 124 TO 129
In a similar manner to Example 123, but starting from the product of
Examples 117 to 122 the following compounds were prepared:
EXAMPLE 124
4-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!naphthoxyacetic acid,
dihydrochloride
The title compound was prepared from the product of Example 117 in 84%
yield: m.p. 253.degree.-255.degree. C.; NMR (D.sub.2 O) .delta.
9.16(1H,d), 8.63(1H,d), 8.42(2H,d), 8.28(1H,d), 8.00(1H,t), 7.78(1H,t),
7.41(2H,d), 7.08(1H,d), 5.27(2H,s), 5.15(2H,s), 4.34(4H,bs), 3.94(4H,bs);
m/e 406 (M+H).sup.+ ; calculated for C.sub.23 H.sub.23 N.sub.3
O.sub.4.2HCl.0.5H.sub.2 O: C, 56.7;H, 5.4; N, 8.6. found: C, 56.8; H, 5.6;
N, 8.1%.
EXAMPLE 125
4-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!-3-methylphenoxyacetic acid,
dihydrochloride
The title compound was prepared from the product of Example 118 in 78%
yield: m.p. 242.degree.-244.degree. C.; NMR (D.sub.2 O) .delta.
8.38(2H,d), 8.00(1H,d), 7.36(2H,d), 7.14(1H,s), 7.10(1H,d), 5.12(2H,s),
4.97(2H,s), 4.30(4H,bs), 3.84(4H,bs), 2.75(3H,s); m/e 370 (M+H).sup.+ ;
calculated for C.sub.20 H.sub.23 N.sub.3 O.sub.4.2HCl. 0.5H.sub.2 O: C,
53.4; H, 5.3; N, 9.3. found C, 53.2; H, 5.8; N, 8.8%.
EXAMPLE 126
3-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!phenoxyacetic acid,
dihydrochloride
The title compound was prepared from the product of Example 119 in 57%
yield: m.p. 190.degree.-193.degree. C.; NMR (D.sub.2 O) .delta.
8.41(2H,d), 7.86(1H,dt), 7.75(1H,t), 7.72(1H,t), 7.57(1H,dm), 7.40(2H,d),
5.26(2H,s), 4.98(2H,s), 4.98(2H,s), 4.32(4H,bs), 3.89(4H,t); m/e 356
(M+H).sup.+ ; calculated for C.sub.19 H.sub.21 N.sub.3
O.sub.4.2HCl.0.75H.sub.2 O: C, 51.7; H, 5.6; N, 9.5. found: C, 51.6; H,
5.8; N, 9.3%.
EXAMPLE 127
4-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!-2-methyl-phenoxyacetic acid,
dihydrochloride
The title compound was prepared from the product of Example 120 in 98%
yield: m.p. 259.degree. to 263.degree. C.; NMR (d.sub.6 DMSO+D.sub.2 O)
.delta. 8.46(2H,d), 7.95(2H,m), 7.38(2H,d), 7.15(1H,d), 5.17(2H,s),
5.00(2H,s), 4.19(4H,s), 3.62(4H,s), 2.39(3H,s); m/e 370 (M+H).sup.+ ;
calculated for C.sub.20 H.sub.23 N.sub.3 O.sub.4.2HCl.0.5H.sub.2 O: C,
53.5; H, 5.8; N, 9.4. found: C, 53.6;H, 5.7; N, 9.5%.
EXAMPLE 128
4-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!-3-methoxy-phenoxyacetic acid,
dihydrochloride
The title compound was prepared from the product of Example 121 in 69%
yield: m.p. 168.degree.-170.degree. C.; NMR (d.sub.6 DMSO+d.sub.4 acetic
acid) .delta. 8.36(2H,d), 7.93(1H,d), 7.28(2H,d), 6.76(1H,d), 6.72(1H,dd),
4.86(2H,s), 4.78(2H,s), 4.08(4H,bs), 3.98(3H,s), 3.54(4H,bs); m/e 386
(M+H).sup.+ ; calculated for C.sub.20 H.sub.23 N.sub.3
O.sub.5.2HCl.2H.sub.2 O; C, 48.7; H, 5.9; N, 8.5. found: C, 48.5; H, 5.7;
N, 8.3%.
EXAMPLE 129
2,2'-4-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!phenylene-1,3-dioxy!diacetic
acid, dihydrochloride
The title compound was prepared from the product of Example 122 in 79%
yield: m.p. 257.degree.-258.degree. C.; NMR (D.sub.2 O) .delta.8.39(2H,d),
8.18(1H,d), 7.48(2H,d), 6.94(1H,dd), 6.76(1H,d), 5.18(2H,s), 5.09(2H,s),
5.01(2H,s), 4.29(4H,b), 3.34(4H,b); m/e 430 (M+H).sup.+ ; calculated for
C.sub.21 H.sub.24 N.sub.3 O.sub.7.2HCl.0.5H.sub.2 O: C, 49.5; H, 5.3; N,
8.2. found, C, 49.4; H, 5.3; N, 7.8%.
EXAMPLE 130
4-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!-2,6-di-tert-butylphenoxyacetic
acid
A solution of methyl
4-(2-4-(4-pyridyl)piperazin-1-yl!acetyl)-2,6-di-tert-butylphenoxyacetate
(241 mg) in dioxane (2.0 ml) was treated with 1N hydrochloric acid and the
mixture heated at 100.degree. C. for 20 hours. The mixture was cooled,
diluted with water, filtered and the filtrate freeze-dried. The solid
residue was purified by flash chromatography on silica eluting with
toluene/ethyl acetate/0.880 ammonia/ethanol (60:20:10:35 v/v/v/v). The
fractions containing the desired product were evaporated, the residue
treated with dioxane, filtered and the filtrate diluted with water and
freeze dried to give a white foam, which on drying at 55.degree. C. gave
the title compound, 90 mg: NMR (d.sub.6 DMSO).delta.8.16(2H,d),
7.97(2H,s), 6.84(2H,d), 4.22(2H,s), 3.86(2H,s), 3.37(4H,t), 2.64(4H,t),
1.39(18H,s); m/e 468 (M+H).sup.+ ; calculated for C.sub.27 H.sub.37
N.sub.3 O.sub.4.2H.sub.2 O: C, 64.4; H, 8.2; N, 8.3. found C, 64.6; H,
7.9; N, 7.9%.
The starting material was prepared as follows:
i) In a similar manner to Example 116i), but starting from
2,5-di-tert-butyl-4-hydroxyacetophenone there was obtained from the ethyl
acetate extracts a brown oil. Flash chromatography on silica, eluting with
successively hexane, then 2% v/v ethyl acetate/hexane and finally 5% v/v
ethyl acetate/hexane gave methyl 4-acetyl-2,6-di-tert-butylphenoxyacetate
in 50% yield as an oil: NMR (d.sub.6 DMSO) .delta.7.84(2H,s), 4.38(2H,s),
3.76(3H,s), 2.55(3H,s), 1.40(18H,s); m/e 321 (M+H).sup.+ ; calculated for
C.sub.19 H.sub.28 O.sub.4 :C, 71.2; H, 8.8. found C, 71.5; H, 9.0%.
ii) In a similar manner to Example 117ii), but starting from the product of
step i) above and with purification by flash chromatography on silica
eluting with 5% v/v ethyl acetate/hexane there was obtained methyl
4-bromoacetyl-2,6-di-tert-butylphenoxyacetate in 82% yield as a yellow
oil: NMR (d.sub.6 DMSO) .delta.7.90(2H,s), 4.92(2H,s), 4.40(2H,s),
3.76(3H,s), 1.41(18H,s).
iii) In a similar manner to Example 5, but starting from the product of
step ii) above and with purification by flash chromatography on silica
eluting successively with dichloromethane then 2 to 5% v/v
methanol/dichloromethane there was obtained a solid. Trituration with
ether gave methyl 4-2-4-(4-pyridyl)piperazin-1-yl!acetyl!-2,6di-
tert-butylphenoxyacetate in 33% yield: m.p. 140.degree.-142.degree. C.;
NMR (d.sub.6 DMSO) .delta.7.97(2H,s), 6.82(2H,d), 4.39(2H,s), 3.85(2H,s),
3.75(3H,s), 3.33(4H,t), 2.64(4H,t), 1.39(18H,s) m/e 482 (M+H).sup.+ ;
calculated for C.sub.28 H.sub.39 N.sub.3 O.sub.4 : C, 69.8; H, 8.2; N,
8.7. found:C, 69.7; H, 8.6; N, 8.1%.
EXAMPLE 131
Ethyl 4-2-4-(4-pyridyl)piperazin-1-yl!acetyl!benzoate
Prepared in a similar manner to Example 5, but starting from ethyl
4-bromoacetylbenozate; recrystallisation from methanol gave the title
compound in 32% yield as pale yellow crystals: m.p.
147.degree.-149.degree. C.; NMR (d.sub.6 DMSO) .delta.8.14(2H,d),
8.08(4H,q), 6.78(2H,d), 4.35(4H,q,AB pattern), 3.98(2H,s), 3.31(4H,t),
2.63(4H,t), 1.35(3H,t); m/e 354 (M+H).sup.30 ; calculated for C.sub.20
H.sub.23 N.sub.3 O.sub.3 : C, 68.0; H, 6.6; N, 11.9. found: C, 68.0;H,
6.5; N, 11.7%.
EXAMPLE 132
Sodium 4-2-4-(4-pyridyl)piperazin-1-yl!acetyl!benzoate
A stirred suspension of the product of Example 131 (353 mg) in methanol (5
ml) was treated with a 1 molar sodium hydroxide solution (3 ml). After 2
hours, the cream coluored solid was collected, washed with a little
methanol and dried to give the title compound, 240 mg, m.p. <300.degree.
C.; NMR (d.sub.6 DMSO) .delta.8.15(2H,d), 8.05(4H,t,AB pattern),
6.85(2H,d), 3.97(2H,s), 3.38(4H,t), 2.65(4H,t), m/e 348 (M+H).sup.+ ;
calculated for C.sub.18 H.sub.18 N.sub.3 NaO.sub.3. 0.25H.sub.2 O: C,
61.4; H, 5.3; N, 11.9. found: C, 61.3; H, 5.2; N, 11.7%.
EXAMPLE 133
Dimethyl
2,2'-5-2-4-(4-pyridyl)piperazin-1-yl!acetyl!phenylene-1,3-dioxy!diaceta
te
In a similar manner to Example 5, but starting from dimethyl
2,2'-(5-bromoacetyl)phenylene-1,3-dioxy!diacetate and with purification
by flash chromatography on silica, eluting with 10% v/v
methanol/dichloromethane, there was obtained a gum. Trituration with
diethyl ether gave the title compound in 14% yield as a yellow solid: m.p.
105.degree.-108.degree. C.; NMR (d.sub.6 DMSO) .delta.8.16(2H,d),
7.15(2H,d), 6.82(3H,m), 4.87(4H,s), 3.89(2H,s), 3.70(6H,s), 3.31(4H,t),
2.63(4H,t); m/e 458 (M+H).sup.+ ; calculated for C.sub.23 H.sub.27 N.sub.3
O.sub.7.0.75H.sub.2 O:C, 58.7; H, 6.1; N, 8.9. found: C, 58.6; H, 6.0; N,
8.5%.
The starting material was prepared as follows:
i) In a similar manner to Example 116i), but starting from
3,5-dihydroxyacetophenone and using 2.2 equivalents of sodium hydride and
methyl bromoacetate there was obtained, after recrystallisation from
iso-propanol, dimethyl 2,2'-(5-acetyl)phenylene-1,3-dioxy!diacetate in
56% yield as a fawn solid: m.p. 96.degree.-98.degree. C.; NMR (CDCl.sub.3)
.delta.7.14 (2H,d), 6.70(1H,t), 4.66(4H,s), 3.81(6H,s), 2.56(3H,s); m/e
296 (M.sup.+), calculated for C.sub.14 H.sub.16 O.sub.7 : C, 56.8; H, 5.4.
found: C, 57.0; H, 5.7%.
ii) In a similar manner to Example 116ii) but starting from the product of
step i) above and with purification by flash chromatography on silica
eluting with ethyl acetate/hexane (1:2 v/v) there was obtained dimethyl
2,2'-5-(bromoacetyl)phenylene-1,3-dioxy!diacetate in 47% yield as a
sticky solid: NMR (CDCl.sub.3) .delta.7.14(2H,d), 6.73(1H,t), 4.66(4H,s),
4.38(2H,s), 3.81(6H,s); m/e 375/377 (M+H).sup.+, 1 Br pattern.
EXAMPLE 134
Disodium
2,2'-5-2-4-(4-pyridyl)piperazin-1-yl!acetyl!phenylene-1,3-dioxy!diaceta
te
A stirred solution of the product from Example 133 (100 mg) in methanol (5
ml) was treated with 1 molar sodium hydroxide solution (0.44 ml) and
stirring continued for 18 hours. Evaporation of the solvent in vacuo and
trituration of the residue with diethyl ether gave the title compound, 86
mg, as a yellow solid: m.p. 184.degree.-206.degree. C.; NMR (D.sub.2 O)
.delta.8.36 (2H,d), 7.29(2H,d), 7.12(2H,d), 6.98(1H,t), 4.72(4H,s),
4.28(2H,s), 3.71(4H,bt), 2.98(4H,bt); m/e 4.74(M+H).sup.+.
EXAMPLE 135
2-4-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!phenoxy!isobutyric acid,
dihydrobromide
A mixture of methyl
2-4-2-4-(4-pyridyl)piperazin-1-yl!acetyl!phenoxy!-isobutyrate (50 mg)
48% w/v hydrobromic acid (0.74 ml), dioxane (1 ml) and water (3 ml) was
heated at 95.degree. C. for 4 hours. The solution was cooled, diluted with
water and freeze-dried to give the title compound, 40 mg, as a pale yellow
solid: m.p. 163.degree.-167.degree. C.; NMR (D.sub.2 O) .delta.8.40(2H,d),
8.16(2H,d), 7.40(2H,d), 7.21(2H,d), 5.21(2H,s), 4.32(4H,b), 3.89(4H,bt),
1.86(6H,s), m/e 384 (M+H).sup.+ ; calculated for C.sub.21 H.sub.25
N.sub.3.2HBr.2H.sub.2 O: C, 43.3; H, 5.3; N, 7.2. found: C, 43.6; H, 5.3;
N, 7.3%.
The starting material was prepared as follows:
i) In a similar manner to Example 116ii) but starting from methyl
2-(4-acetylphenoxy)isobutyrate and purification by flash chromatography on
silica, eluting with ethyl acetate/hexane (1:2 v/v), there was obtained
methyl 2-(4-bromoacetylphenoxy)-isobutyrate in 45% yield as an orange oil:
NMR (CDCl.sub.3) .delta.7.91(2H,d), 6.85(2H,d), 4.48(2H,s), 3.76(3H,s),
1.67(6H,s). m/e 315/317 (M+H).sup.+ 2 Br pattern.
ii) The product from step (i) above (2.00 g) in acetonitrile (10 ml) was
added dropwise over 15 minutes to a stirred solution of
1-(4-pyridyl)piperazine (1.04 g) and triethylamine (0.89 ml) in
acetonitrile (15 ml) and the mixture stirred overnight. The precipitated
solid was removed by filtration and the filtrate evaporated. Purification
of the residue by flash chromatography on silica, eluting with 0 to 5% v/v
methanol/dichloromethane, gave a yellow gum. Trituration of this gum with
diethyl ether gave methyl
2-4-2-4-(4-pyridyl)piperazin-1-yl!acetyl!phenoxy!isobutryate, 170 mg,
as a white solid: m.p. 88.degree.-90.degree. C.; NMR (d.sub.6
DMSO).delta.8.15(2H,d), 7.96(2H,d), 6.82(4H,m), 3.92(2H,s), 3.70(3H,s),
3.33(4H,t), 2.63(4H,t), 1.60(6H,s); m/e 398 (M+H).sup.+ ; calculated for
C.sub.22 H.sub.27 N.sub.3 O.sub.4.0.25H.sub.2 O: C, 65.8; H, 6.8; N, 10.5.
found: C, 65.8 H, 7.1; N, 10.4%.
EXAMPLE 136
Ethyl-4-2-4-(4-pyridyl)piperazin-1-yl!acetyl!phenoxyacetate
Ethyl 4-bromoacetylphenoxyacetate (6.0 g) was added to a stirred, cooled
(4.degree. C.) solution of 1-(4-pyridyl)piperazine (6.5 g) in acetonitrile
(225 ml). Stirring was continued for 1 hour at 4.degree. C., then
overnight at ambient temperature when the precipitated solid was removed
by filtration. The filtrate was evaporated in vacuo and the solid residue
triturated with water, filtered, then washed with water and dried.
Recrystallization from a small volume of ethanol gave the title compound,
1.71 g, as a cream coloured solid: m.p. 113.degree.-114.degree. C.; NMR
(d.sub.6 DMSO) .delta.8.15(2H,d), 7.98(2H,d), 7.02(2H,d), 6.80(2H,d),
4.89(2H,d), 4.17(2H,q), 3.84(2H,s), 3.32(4H,t), 2.62(4H,t) 1.22(3H,t); m/e
384 (M+H).sup.+ ; calculated for C.sub.21 H.sub.25 N.sub.3 O.sub.4 : C,
65.8; H, 6.6; N, 11.0. found: C, 65.5; H, 6.6; N, 10.8%.
The starting material was prepared as follows:
i) In a similar manner to Example 118i), but starting from ethyl
bromoacetate there was prepared ethyl 4-acetylphenoxyacetate as a
crystalline solid in quantitative yield. The product was used without
further purification.
ii) In a similar manner to Example 117ii), but starting from the product of
step i) above there was prepared ethyl 4-bromoacetylphenoxyacetate in 47%
yield as a solid: m.p. 41.degree.-42.degree. C.; NMR (d.sub.6 DMSO)
.delta.7.90(2H,d), 7.05(2H,d), 4.90(2H,s), 4.72(2H,s), 4.18(2H,q),
1.33(3H,t).
EXAMPLE 137
iso-Propyl 4-2-4-(4-pyridyl)piperazin-1-yl!acetyl!phenoxyacetate
iso-Propyl 4-bromoacetylphenoxyacetate (6.3 g) was added to a stirred,
cooled (4.degree. C.) solution of 1-(4-pyridyl)piperazine (6.5 g) in
acetonitrile (225 ml). Stirring was continued for 1 hour at 4.degree. C.,
then overnight at ambient temperature when the precipitated solid was
removed. The filtrate was evaporated in vacuo and the residue positioned
between ethyl acetate and water. The organic phase was dried (MgSO.sub.4)
and evaporated. Purification by flash chromatography on silica, eluting
firstly with 0 to 10% v/v methanol/dichloromethane and then toluene/ethyl
acetate/0.880 ammonium hydroxide/ethanol (60:20:10:35 v/v/v/v), gave a
cream solid. Recrystallisation from iso-propanol gave the title compound,
2.1 g: m.p. 121.degree.-122.degree. C.; NMR (d.sub.6 DMSO)
.delta.8.14(2H,d), 7.98(2H,d), 7.02(2H,d), 6.80(2H,d), 4.99(1H,m),
4.85(2H,s), 3.84(2H,s), 3.33(4H,t), 2.62(4H,t), 1.22(6H,d); m/e 398
(M+H).sup.+ ; calculated for C.sub.22 H.sub.27 N.sub.3 O.sub.4 : C, 66.5;
H, 6.9; N, 10.6. found: C, 65.8; H, 6.8; N, 10.4%.
The starting material was prepared as follows:
i) In a similar manner to Example 118i), but starting from iso-propyl
bromoacetate there was prepared iso-propyl 4-acetylphenoxyacetate as a
crystalline solid in quantitative yield. The product was used without
further purification.
ii) In a manner similar to Example 117ii), but starting from the product of
step i) above and using iso-propyl acetate in place of ethyl acetate as
solvent, there was prepared iso-propyl 4-bromoacetylphenoxyacetate as a
crystalline solid in 69% yield: m.p. 64.degree.-66.degree. C.; NMR
(d.sub.6 DMSO) .delta.7.98(2H,d), 7.06(2H,d), 4.99(1H,m), 4.88(2H,s),
4.83(2H,s), 1.22(6H,d).
EXAMPLE 138
tert-Butyl 4-2-4-(4-pyridyl)piperazin-1-yl!acetyl!-phenoxyacetate
Prepared in a similar manner to Example 136, but starting from tert-butyl
4-bromoacetylphenoxyacetate. After evaporation of the acetonitrile
solution the residue was purified by column chromatography on silica,
eluting with 0 to 5% v/v methanol/dichloromethane, to give a yellow oil.
Trituration with diethyl ether gave the title compound in 35% yield as a
solid: m.p. 103.degree.-104.degree. C.; NMR (d.sub.6 DMSO)
.delta.8.15(2H,d), 7.98(2H,d), 7.00(2H,d), 6.82(2H,d), 4.76(2H,s),
3.84(2H,s), 3.37(4H,t), 2.62(4H,t), 1.43(9H,s); m/e 412 (M+H).sup.+
calculated for C.sub.23 H.sub.29 N.sub.3 O.sub.4 : C, 67.1; H, 7.1; N,
10.2. found: C, 66.9; 7.3; N, 10.0%.
The starting material was prepared as follows:
i) In a similar manner to Example 118i), but starting from tert-butyl
bromoacetate there was prepared tert-butyl 4-acetylphenoxyacetate as a
crystalline solid in 90% yield: m.p. 59.degree.-61.degree. C.; NMR
(d.sub.6 DMSO+d.sub.4 acetic acid) .delta.7.94(2H,d), 6.98(2H,d),
4.21(2H,s), 2.52(3H,s), 1.44(9H,s).
ii) A solution of the product from step i) above (3.3 g) and
N-bromosuccinimide (2.35 g) in carbon tetrachloride was heated at reflux
temperature for 80 hours. After cooling, the precipitate was removed by
filtration and the filtrate concentrated in vacuo. Purification of the
residual oil by flash chromatography on silica, eluting with 5% v/v ethyl
acetate/toluene, gave tert-butyl 4-bromoacetylphenoxyacetate, 1.9 g, as a
crystalline solid: m.p. softens at 110.degree.-116.degree. C.; NMR
(d.sub.6 DMSO) .delta.7.97(2H,d), 7.04(2H,d), 4.84(2H,s), 4.80(2H,s),
1.43(9H,s).
EXAMPLE 139
Neopentyl 4-2-4-(4-pyridyl)piperazin-1-yl!acetyl!phenoxyacetate
Prepared in a similar manner to Example 136, but starting from neopentyl
4-bromoacetylphenoxyacetate. After evaporation of the aceonitrile
filtrate, the residue was purified by flash chormatography on silica,
eluting with 0 to 5% v/v methanol dichloromethane, to give an oil.
Trituration with diethyl ether/hexane gave the title compound in 23% yield
as a solid: m.p. 88.degree.-90.degree. C.; NMR (d.sub.6 DMSO)
.delta.8.14(2H,d), 7.98(2H,d), 7.04(2H,d), 6.81(2H,d), 4.97(2H,s),
3.83(4H,s), 3.32(4H,t), 2,61(4H,t), 0.86(9H,s); m/e 426 (M+H).sup.+ ;
calculated for C.sub.24 H.sub.31 N.sub.3 O.sub.4 : C, 67.7; H, 7.3; N,
9.9. found: C, 68.1; H, 7.4; N, 9.9%.
The starting material was prepared as follows:
i) To a stirred suspension of 4-acetylphenoxyacetic acid (4.36 g) in
dichloromethane (50 ml) was added oxalyl chloride (2.36 ml) and DMF (one
drop). The mixtutre was stirred for one hour and then the solvent removed
in vacuo to give a yellow oil (4.8 g). A solution of this oil in diethyl
ether was added dropwise to a stirred solution of neopentyl alcohol (2.18
g) and triethylamine (3.4 ml) in diethyl ether (50 ml). After the
addition, stirring was continued for a further 18 hours when the
precipitated solid was removed by filtration. Evaporation of the filtrate
and purification of the residue by flash chromatography on silica, eluting
with dichloromethane, gave neopentyl 4-acetylphenoxyacetate, 5.1 g, as a
pale yelow oil: NMR (CDCl.sub.3) .delta.7.94(2H,d), 6.95(2H,d),
4.72(2H,s), 3.91(2H,s), 2.56(3H,s), 0.93(9H,s).
ii) To a stirred solution of the product step i) above (2.64 g) in
chloroform (25 ml), was added slowly over 10 minutes, a solution of
bromine (0.52 ml) in chloroform (10 ml). Stirring was continued for a
further hour and the solvent removed in vacuo. Trituration of the residue
with diethyl ether/hexane gave neopentyl 4-bromoacetylphenoxyacetate, 2.3
g, as a crystalline solid: m.p. 85.degree.-87.degree. C.
EXAMPLE 140
Dimethyl 4-2-4-(4-pyridyl)piperazin-1-yl!acetyl!phenoxymalonate
Prepared in a similar manner to Example 136, but starting from dimethyl
4-bromoacetylphenoxymalonate and after evaporation of the aceonitrile
filtrate the residue was partitioned between water/ dichloromethane. The
organic solution was dried (MgSO.sub.4), concentrated and purification by
flash chromatography, eluting with 0 to 5% v/v methanol/dichloromethane,
then trituration with diethyl ether gave the title compound in 31% yield
as a pale yellow solid: m.p. 115.degree.-116.degree. C.; NMR (d.sub.6
DMSO) .delta.8.16(2H,d), 8.02(2H,d), 7.09(2H,d), 6.82(2H,d), 5.95(1H,s),
3.86(2H,s), 3.80(6H,s), 3.34(4H,t), 2.63(4H,t), m/e 428 (M+H).sup.+ ;
calculated for C.sub.22 H.sub.25 N.sub.3 O.sub.6 : C, 61.8; H, 5.9; N,
9.8. found C, 61.3; H, 5.9; N, 9.2%.
The starting material was prepared as follows:
i) In a similar manner to Example 118i), but starting from dimethyl
bromomalonate and purification by flash chromatography on silica, eluting
with 50 to 75% v/v diethyl ether/hexane, there was prepared dimethyl
4-acetylphenoxymalonate in 53% yield as a white crystalline solid: m.p.
71.degree.-72.degree. C.; NMR (d.sub.6 DMSO) .delta.7.95(2H,d),
7.09(2H,d), 5.95(1H,s), 3.78(6H,s), 2.53(3H,s); m/e 267 (M+H).sup.+ ;
calculated for C.sub.13 H.sub.14 O.sub.6 : C, 58.6; H, 5.3. found: C,
58.9; H, 5.3%.
ii) In a similar manner to Example 117ii), but starting from the product of
step i) above and using methyl acetate in place of ethyl acetate as
solvent, there was prepared methyl 4-bromoacetylphenoxymalonate in 59%
yield as a white crystalline solid: m.p. 114.degree.-115.degree. C.; NMR
(d.sub.6 DMSO) .delta.7.99(2H,d), 7.12(2H,d), 5.99(1H,s), 4.86(2H,s),
3.80(6H,s).
EXAMPLE 141
5-4-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!phenoxymethyl!tetrazole
A mixture of 5-(4-chloroacetylphenoxymethyl)tetrazole (166 mg) and
1-(4-pyridyl)piperazine (214 mg) in acetonitrile (10 ml) was stirred
overnight. The precipitate was collected, washed with acetonitrile and
dried. A solution of this material in a small volume of 50% v/v acetic
acid/water was transfered to a 1 inch preparative reverse phase hplc
column (DYNAMAX (Trade Mark) C18 83-221-C) and eluted with
water/acetonitrile/ trifluoroacetic acid in a gradient from 98:2:0.1 v/v/v
to 60:40:0.1 v/v/v. The pure fractions, on freeze-drying, gave the title
compound, 8.1 mg, as a white powder: NMR (D.sub.2 O) .delta.8.39 (2H,d),
8.18(2H,d), 7.40(4H,m), 5.84(2H,s), 5.20(2H,s), 4.31(4H,bt), 3.87(4H,bt);
m/e 380 (M+H).sup.+
The starting material was prepared as follows:
ii) A mixture of phenoxyacetonitrile (26.6 g), sodium azide 13.0 g and
ammonium chloride (10.6 g) in DMF (80 ml) was heated at reflux temperature
for 18 hours. The solvent was removed in vacuo and the black solid
triturated with diethyl ether, collected and dissolved in 4 molar sodium
hydroxide solution. This solution was extracted with diethyl ether, then
treated with charcoal and filtered. The filtrate, on acidification with
concentrated hydrochloric acid, gave a white precipitate.
Recrystallisation from toluene gave 5-(phenoxymethyl)tetrazole, 12.05 g,
as white plates: m.p. 128.degree.-131.degree. C.; NMR (d.sub.6
DMSO).delta.7.31(2H,m), 7.02(3H,m), 5.47(2H,s); m/e 177 (M+H).sup.+ ;
calculated for C.sub.8 H.sub.8 N.sub.4 O: C, 54.5; H, 4.6; N, 31.8. found:
C, 54.6; H, 4.6; N, 32.0%.
ii) Aluminum chloride (30.3 g) was added to a stirred mixture of the
product of step i) above (10 g) and chloroacetyl chloride (19.3 g) in dry
1,2-dichloroethane and stirring continued overnight. The mixture was
concentrated to about half volume on the steam bath, cooled and added to
an ice/hydrochoric acid mixture. After stirring for 15 minutes the solid
was collected and, on recrystallisation from methanol/water, gave
5-(4-chloroacetylphenoxymethyl)tetrazole, 7.5 g: m.p.
194.degree.-196.degree. C.; NMR (d.sub.6 DMSO) .delta.7.99(2H,d),
7.20(2H,d), 5.61(2H,s), 5.11(2H,s); m/e 251 (M-H)-, 1 Cl pattern;
calculated for C.sub.10 H.sub.9 ClN.sub.4 O.sub.2 : C, 47.5; H, 3.6; N,
22.2. found: C, 43.7; H, 3.7; N, 22.2%.
EXAMPLE 142
4-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!phenoxyacetamide
A solution of the product of Example 1 (200 mg) in methanol (10 ml),
prepared under argon, was cooled to 4.degree. C. and saturated with dry
ammonia gas, then sealed in a pressure bottle and kept for 2 days. The
orange crystals which formed, after filtration and washing with a little
methanol, gave the title compound, 140 mg: m.p. 247.degree. to 248.degree.
C.; NMR (d.sub.6 DMSO).delta.8.16(2H,d), 7.99(2H,d), 7.55(1H,bs),
7.37(1H,bs), 7.02(2H,d), 6.81(2H,d), 4.54(2H,s), 3.85(2H,s), 3.33(4H,t),
2.60(4H,t); m/e 355 (M+H).sup.+ ; calculated for C.sub.19 H.sub.22 N.sub.4
O.sub.3 : C, 64.4; H, 6.3; N, 15.8. found: C, 64.4; H, 6.4; N, 15.6%.
EXAMPLE 143
2-4-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!phenoxy!-N-methylacetamide
A suspension of the product of Example 1 (100 mg) in a 33% w/v solution of
methylamine in ethanol (3 ml) was stirred for 18 hours. The solid formed,
after filtration and washing with a little ethyl acetate, gave the title
compound, 65 mg: m.p. 169.degree.-171.degree. C.; NMR (d.sub.6
DMSO).delta.8.14(2H,d), 8.06(1H,bq), 8.00(2H,d), 7.05(2H,d), 6.80(2H,d),
4.56(2H,s), 3.82(2H,s), 3.30(4H,t), 2.66(3H,d), 2.61(4H,t); m/e 369
(M+H).sup.+ ; calculated for C.sub.20 H.sub.24 N.sub.4 O.sub.3 : C, 65.2;
H, 6.6; N, 15.2. found: C, 65.0; H, 6.8; N, 15.1%.
EXAMPLE 144
2-4-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!phenoxy!-N-(2-methoxymethyl)-ac
etamide
A suspension of the product of Example 1, (100 mg) in 2-methoxyethylamine
(1 ml) was stirred for 18 hours. Filtration of the solid and washing with
ethyl acetate gave the title compound, 70 mg, as a white crystalline
solid: m.p. 142.degree.-145.degree. C.; NMR (d.sub.6 DMSO+d.sub.4 acetic
acid) .delta.8.20(2H,d), 8.00(2H,d), 7.14(2H,d), 7.06(2H,d), 4.62(2H,s),
3.72(4H,t), 3.38(4H,m), 3.26(3H,s), 2.78(4H,t); m/e 413 (M+H).sup.+ ;
calculated for C.sub.22 H.sub.28 N.sub.4 O.sub.4 : C, 64.1; H, 6.8; N,
13.6. found: C, 63.9; H, 6.8; N, 13.3%.
EXAMPLE 145
2-4-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!phenoxy!-N-(phenylmethyl)-aceta
mide
A solution of 2-4-(bromoacetyl)phenoxy!-N-(phenylmethyl)acetamide (1.40 g)
(preparation described in EPO 052442) in acetonitrile (5 ml) was added to
a stirred solution of 1-(4-pyridyl)piperazine (1.14 g) in acetonitrile (20
ml). After stirring overnight the liquors were decanted from the residual
gum, then concentrated in vacuo. Purification by flash chromatography on
silica, eluting with 2 to 5% v/v methanol/dichloromethane, gave a solid.
Trituration of this solid with diethyl ether gave the title compound, 95
mg: m.p. 150.degree.-151.degree. C.; NMR (d.sub.6 DMSO) .delta.8.67(1H,bt)
8.15(2H,d), 8.00(2H,d), 7.26(5H,m), 7.06(2H,d), 6.81(2H,d), 4.66(2H,s),
4.34(2H,d), 3.84(2H,s), 3.33(4H,t), 2.54(4H,t); m/e 445 (M+H).sup.+ ;
calculated for C.sub.26 H.sub.28 N.sub.4 O.sub.3. 0.25H.sub.2 O: C, 69.5;
H, 6.4; 12.5. found: C, 69.6; H, 6.4; N, 12.3%.
EXAMPLE 146
Methyl N-4-2-4-(4-pyridyl)piperazin-1-yl!acetyl!phenoxyacetyl!glycinate
A solution of methyl N-4-(bromoacetyl)phenoxyacetyl!glycinate (0.85 g) in
acetonitrile (10 ml) was added to a stirred solution of
1-(4-pyridyl)piperazine (0.81 g) in acetonitrile (30 ml). After stirring
overnight the solvent was removed in vacuo and the residue partitioned
between water/ethyl acetate. The organic phase was washed with water, then
dried (MgSO.sub.4) and evaporated. The residue was purified by flash
chromatography on silica, eluting with 0 to 7.5% v/v
methanol/dichloromethane. Evaporation of the fractions gave the title
compound, 130 mg, as a foam: NMR (d.sub.6 DMSO) .delta.8.58(1H,t)
8.16(2H,d), 8.01(2H,d), 7.08(2H,d), 6.83(2H,d), 5.75(1H,s), 4.68(2H,s),
3.92(2H,d), 3.84(2H,s), 3.65(3H,s), 3.34(4H,t+H.sub.2 O), 2.65(4H,t); m/e
427 (M+H).sup.+ ; calculated for C.sub.22 H.sub.26 N.sub.4 O.sub.5.
0.5CH.sub.2 Cl.sub.2 : C, 57.6; H, 5.8; N, 11.9. found: C, 57.8; H, 5.7;
N, 12.0%.
The starting material was prepared as follows:
i) To a stirred suspension of 4-(acetyl)phenoxyacetic acid (3.00 g) in
dichloromethane (40 ml) was added oxalyl chloride (1.62 ml) and 1 drop of
DMF. Stirring was continued for 1.5 hours and the clear solution on
evaporation gave an oil (I). Triethylamine (4.30 ml) was added slowly to a
stirred, cooled (4.degree. C.) suspension of methyl glycinate
hydrochloride (1.95 g) in dichloromethane (25 ml) under argon. After
stirring for 10 minutes, a solution of (I) in dichloromethane (10 ml) was
added and stirring continued for a further 2 hours. The precipitate was
removed by filtration and the filtrate concentrated in vacuo. Purification
of the residue by flash chromatography on silica, eluting with 2% v/v
methanol/ dichloromethane, gave a solid. Trituration with ether/hexane
gave methyl N-4-(acetyl)phenoxyacetyl!glycinate, 3.1 g, as white
crystals: m.p. 120.degree.-121.degree. C.; NMR (d.sub.6
DMSO).delta.8.57(1H,t), 7.94(2H,d), 7.07(2H,d), 4.66(2H,s), 3.92(2H,s),
3.64(3H,s), 2.52(3H,s); m/e 266 (M+H).sup.+ ; calculated for C.sub.13
H.sub.15 NO.sub.5 : C, 58.9; H, 5.7; N, 5.3. found: C, 58.4; H, 5.5; N,
5.0%.
ii) The product of step i) (3.00 g) and N-bromosuccinimide (2.02 g) in
carbon tetrachloride (50 ml) was heated at reflux temperature for 64
hours. The solvent was evaporated and the black residue dissolved in
methanol/ethyl acetate, treated with charcoal, filtered and then
evaporated. The resulting brown oil was purified by flash chromatography
on silica, eluting with dichloromethane. Trituration with hexane gave
methyl N-4-(bromoacetyl)phenoxyacetyl!glycinate, 0.85 g, as a solid: mp
softens 109.degree.-111.degree. C.; NMR (d.sub.6 DMSO) .delta.8.60(1H,bt),
7.99(2H,d), 7.09(2H,d), 4.84(2H,s), 4.69(2H,s), 3.91(2H,d), 3.64(3H,s).
EXAMPLE 147
Methyl 4-2-4-(4-pyridyl)piperazin-1-yl!ethyl!phenoxyacetate
A mixture of methyl 4-1-(2-methanesulphonyloxyethyl)!phenoxyacetate (2.0
g) and 1-(4-pyridyl)piperazine (2.26 g) in acetonitrile was heated at
reflux temperature for 25 hours. The solvent was removed in vacuo and the
residue purified by flash chromatography on silica, eluting with
successively 2.5, 3, 3.5, and 4% v/v methanol/dichloromethane. Isolation
of the desired fractions and trituration with diethyl ether gave the title
compound, 600 mg: recrystallisation from methanol gave white crystals,
m.p. 104.degree.-105.degree. C.; NMR (d.sub.6 DMSO).delta.8.15(2H,d),
7.15(2H,d), 6.86(2H,d), 6.82(2H,d), 4.74(2H,s), 3.69(3H,s), 3.30(4H,t. 2H,
m. +H.sub.2 O), 2.71(2H,m), 2.54(4H,t), m/e 356 (M+H).sup.+, calculated
for C.sub.20 H.sub.25 N.sub.3 O.sub.3. 0.25H.sub.2 O: C, 66.7; H, 7.1; N,
11.7. found: C, 67.0; H, 7.2; N, 11.4%.
The starting material was prepared as follows:
i) A mixture of 4-hydroxyphenethyl alcohol (5.37 g), anhydrous potassium
carbonate (5.37 g) and methyl bromoacetate (3.80 ml) in anhydrous acetone
(50 ml) was stirred for 18 hours. The mixture, after fitration, was
evaporated and the residue after purification by flash chromatography on
silica, eluting with 2% v/v methanol/dichloromethane, gave methyl
4-1-(2-hydroxyethyl)!phenoxyacetate, 5.05 g, as an oil: NMR (CDCl.sub.3)
.delta.7.15(2H,d), 6.86(2H,d), 4.62(2H,s), 3.84(2H,m), 3.80(3H,s),
2.81(2H,t), 1.40(1H,bt); m/e 210 (M).sup.+ ; calculated for C.sub.11
H.sub.14 O.sub.4 : C, 62.8; H, 6.7. found: C, 62.8; H, 6.8%.
ii) Methanesulphonyl chloride (0.98 ml) was added dropwise, over 30
minutes, to a stirred, cooled (4.degree. C.) solution of the product from
step i) (2.22 g) and triethylamine (1.91 ml) in dichloromethane (35 ml)
under argon. After 2 hours, the solvent was evaporated and the residue
partitioned between ethyl acetate (75 ml) and water (20 ml). The organic
phase was separated, washed with saturated sodium chloride solution
(3.times.15 ml), dried and evaporated. The residue on purification by
flash chromatography on silica, eluting with 45% v/v ethyl acetate/hexane,
gave methyl 4-1-(2-methanesulphonyloxyethyl)!phenoxyacetate, 2.85 g, as
an oil: NMR (CDCl.sub.3).delta.7.16(2H,d), 6.87(2H,d), 4.62(2H,s),
4.38(2H,t), 3.81(3H,s), 3.00(2H,t), 2.85(3H,s); m/e 288 (M.sup.+);
calculated for C.sub.12 H.sub.16 O.sub.6 S: C, 50.0; H, 5.6; S, 11.1
found: C, 50.1; H, 5.5; S, 11.0%.
EXAMPLE 148
4-2-4-(4-Pyridyl)piperazin-1-yl!ethyl!phenoxyacetate acid dihydrochloride
In a similar manner to Example 123, but starting from the product of
Example 147, there was obtained the title compound in 95% yield: m.p.
270.degree.-273.degree. C.; NMR (d.sub.6 DMSO +d.sub.4 acetic acid)
.delta.8.34(2H,d), 7.30(2H,d), 7.22(2H,d), 6.91(2H,d), 4.67(2H,s),
4.06(4H,b), 3.46(4H,b), 3.35(2H,m), 3.05(2H,m); m/e 342 (M+H).sup.+ ;
calculated for C.sub.19 H.sub.22 N.sub.3 O.sub.3.2HCl: C, 55.0; H, 6.5; N,
10.1. found: C, 54.8; H, 6.2; N, 9.8%.
EXAMPLE 149
Tertiary butyl
4-2-4-(4-pyridyl)piperazin-1-yl!carbonylmethyl!-phenoxyacetate
In a similar manner to Example 18iv) but starting from tertiary butyl
4-(carboxymethyl)phenoxyacetate, there was obtained after flash
chromatography on silica, eluting with 0 to 5% v/v
methanol/dichloromethane, a gum. Further purification by flash
chromatography on neutral alumina, eluting with 1% v/v
methanol/dichloromethane followed by trituration with diethyl ether gave
the title compound in 17% yield as a white solid: m.p.
110.degree.-112.degree. C.; NMR (d.sub.6 DMSO) .delta.8.22(2H,d),
7.15(2H,d), 7.06(2H,d), 6.83(2H,d), 4.60(2H,s), 3.70(2H,s), 3.62(4H,bt),
3.38(4H, bt +H.sub.2 O) 1.42(9H,s), m/e 412 (M+H).sup.+ ; calculated for
C.sub.23 H.sub.29 N.sub.3 O.sub.4.0.25H.sub.2 O: C, 66.4; H, 7.1; N, 10.1.
found: C, 66.4; H, 7.2; N, 10.1%.
The starting material was prepared as follows:
ii) Sodium hydride (50% w/w dispersion in mineral oil, 3.7 g) was treated
under argon with repeated washes of hexane. The oil-free residue was
suspended in dry DMF (100 ml) and 4-hydroxyphenylacetic acid (13.0 g) was
added portionwise to the stirred cooled (4.degree. C.) mixture. After 30
minutes, benzyl bormide (9.2 ml) was added dropwise and, after a further 1
hour at 4.degree. C., stirring was continued overnight at ambient
temperature. The solvent was evaporated in vacuo and the residue
partitioned between ethyl acetate and water. The aqueous phase was
re-extracted with further ethyl acetate and the combined organic extracts
washed with water and brine, then dried (MgSO.sub.4) and evaporated. The
crystaline residue gave benzyl 4-hydroxyphenylacetate, 17.8 g, as
off-white crystals: m.p. 70.degree.-72.degree. C. NMR (CDCl.sub.3)
.delta.7.32(5H,m), 7.14(2H,d), 6.76(2H,d), 5.12(2H,s), 3.59(2H,s); m/e 242
(M.multidot.).sup.+.
ii) Sodium hydride (50% w/w dispersion in mineral oil, 2.1 g) was treated
under argon with repeated washes of hexane. The oil-free residue was
suspended in dry DMF (130 ml) and the product from step i) (10 g) added in
three portions to the cooled (4.degree. C.) stirred mixture. Stirring was
continued for a further 15 minutes when tertiary butyl bromoacetate (7.0
ml) was added dropwise over 15 minutes. After 1 hour at 40.degree. C., the
mixture was stirred for 6 hours at ambient temperature. The solvent was
evaporated in vacuo and the residue partitioned between ethyl acetate and
water. The aqueous phase was re-extracted with further ethyl acetate and
the combined organic phases washed with water and brine, then dried
(MgSO.sub.4) and evaporated. The residue, after purification by flash
chromatogrpahy on silica eluting with dichloromethane, gave tertiary butyl
4-(benzyloxycarbonylmethyl)phenoxyacetate, 7.5 g, as a colourless oil: NMR
(CDCl.sub.3) 7.31(5H,m), 7.20 (2H,m), 5.12(2H,s), 4.49(2H,s) 3.60(2H,2),
1.48(9H,s); m/e 356 (M.multidot.).sup.+.
iii) In a similar manner to Example 18iii) but starting from the product of
step ii) above was prepared tertiary butyl 4-(carboxymethyl)phenoxyacetate
in 96% yield as a white crystalline solid: m.p. 78.degree.-80.degree. C.
NMR (d.sub.6 DMSO) .delta.7.15(2H,d), 6.82(2H,d), 4.60(2H,s), 3.48(2H,s),
1.43(9H,s); m/e 266 (M.multidot.).sup.+ ; calculated for C.sub.14 H.sub.18
O.sub.5.0.75H.sub.2 O: C, 60.1; H, 7.0. found: C, 59.9; H, 7.2%.
EXAMPLE 150
4-2-4-(4-Pyridyl)piperazin-1-yl!carbonylmethyl!phenoxyacetic acid,
dihydrochloride
A solution of the product from Example 149 (50 mg) in a mixture of dioxane
(1 ml), water (2 ml) and 1 molar hydrochloric acid solution (0.61 ml) was
heated overnight at 90.degree. C. The resulting solution, on dilution with
water and freeze-drying, gave the title compound, 30 mg, as a yellow foam:
NMR (d.sub.6 DMSO+d.sup.4 acetic acid) .delta. 8.31 (2H,d), 7.24(2H,d),
7.18(2H,m), 6.87(2H,m), 4.64(2H,s), 3.96(4H,t), 3.72(2H,s), 3.32(4H,t);
m/e 356 (M+H).sup.+ ; calculated for C.sub.19 H.sub.21 N.sub.3
O.sub.4.2HCl.2.5H.sub.2 O; C, 48.2; H, 5.9; N, 8.9. found C, 48.5; H, 6.0;
N, 8.8%.
EXAMPLE 151
Methyl 4-2-4-(2-methylpyrid-4-yl)piperazin-1-yl!acetyl!phenoxyacetate
Methyl 4-bromoacetylphenoxyacetate (1.72 g) was added to a stirred mixture
of 1-4-(2-methylpyridyl)!piperazine dihydrochloride (1.5 g) and
triethylamine (2.5 ml) in acetonitrite (25 ml). Stirring was continued
overnight when the solvent was removed in vacuo. Purification by flash
chromatography, first on silica eluting with 10% v/v
methanol/dichloromethane and then on neutral alumina eluting with 1%
methanol/dichloromethane, gave the title compound, 418 mg, as a white
solide: m.p. 155.degree.-157.degree. C; NMR (d.sub.6
DMSO).delta.8.00(3H,m), 7.04(2H,d), 6.70(1H,d), 6.64(1H, dd), 4.92(2H,s),
3.83(2H,s), 3.71(3H,s), 3.30(4H b+H.sub.2 O), 2.61)4H,t), 2.32(3H,s); m/e
384 (M+H).sup.+ ; calculated for C.sub.21 H.sub.25 N.sub.3 O.sub.4 : C,
65.8; H, 6.6; N, 11.0. found: C, 65.4; H, 6.8; N, 10.9%.
The starting material was prepared as follows:
i) A mixture of 4-chloro-2-picoline (5 g) and 1-benzylpiperazine (13.6 ml)
in xyelen (50 ml was heated at reflux temerature for 18 hours. The
solution was cooled and the solid precipitate removed by filtration and
the filtrate concentrated in vacuo. Purification by flash chromatography
on silica, eluting with 20% v/v methanol/dichloromethane gave
4-4-(2-picoyly)!-1-benzylpiperazine, 9.54 g, as a light fawn crystalline
solid: m.p. 94.degree.-95.degree. C.; NMR (CDCl.sub.3).delta.8.15(1H,d),
7.30(5H,m), 6.51(2H,m), 3.57(2H,s), 3.44(4H,t), 2.57(4H,t), 2.46(3H,s);
m/e 268 (M+H).sup.+ ; calculated for C.sub.17 H.sub.21 N.sub.3 : C, 76.4;
H, 7.9; N, 15.7. found: C, 75.7; H, 8.1; N, 15.7%.
ii) 10% w/w Palladium on charcoal (1.5 g) was added to a stirred solution
of the product of step i) (9.00 g) and 2 molar hydrochloric acid (34 ml)
in methanol 180 ml) and the mixture was hydrogenated at room temperature
and pressure until the theoretical amount of hydrogen had been taken up.
Charcoal was added, the mixture stirred for 5 minutes then filtered
through diatomaceous earth and the filtrate on evaporation to dryness gave
1-4-(2-methylpyridyl)!piperazine dihydrochloride, 10.6 g, as a fawn
solid: m.p 64.degree.-68.degree. C. NMR (d.sub.6 DMSO).delta.8.20(1H,d),
7.18(1H,d), 7.12(1H,dd), 3.92(4H,t), 3.19(4H,t), 2.51(3H,s+DMSO); m/e 178
(M+H).sup.+ ; calculated for C.sub.10 H.sub.15 N.sub.3.2HCl.0.75H.sub.2 O:
C, 45.5; H, 7.0; N, 15.9. found: C, 45.3; H, 7.0; N, 15.8%.
EXAMPLES 152
4-2-4-(2-Methylpyrid-4-yl)piperazin-1-yl!acetyl!phenoxyacetic acid,
dihydrobromide
A mixture of the product of Example 151 (160 mg), 48% w/v hydrobromic acid
(0.25 ml) and dioxane (1 ml) in water (3 ml) were heated at 90.degree. C.
for 30 minutes. The solution was cooled, further water added and the
mixture freeze-dried. Trituration of the residue with absolute ethanol
gave the title compound, 50 mg, as a fawn solid: m.p.
146.degree.-148.degree. C.; NMR (d.sub.6 DMSO+d.sub.4 acetic
acid).delta.8.17(1H,d), 7.95(2H,d), 7.09(4H,m), 4.94(2H,s), 4.78(2H,s),
3.99(4H,b), 3.07(1H,q), 2.46(3H,s), 1.17(1.5H,t); m/e 370 (M+H).sup.+ ;
calculated for C.sub.20 H.sub.23 N.sub.3 O.sub.4.2HBr.H.sub.2 O.0.5C.sub.2
H.sub.5 H: C, 44.1; H, 5.3; N, 7.3, found: C, 44.0; H, 5.4; N, 7.2%
EXAMPLE 153
Methyl 2-4-(2,6-dimethylpyrid-4-yl)piperazin-1-yl!acetyl!phenoxyacetate,
hydrobromide
Prepared in a similar manner to Example 151, but starting from
1-4-2,6-dimethylpyridyl)!piperazine and using only one equivalent of
triethylamine. Purification by flash chromatography on silica eluting with
0 to 5% v/v methanol/dichloromethane, followed by trituration with diethyl
ether, gave the title compound in 64% yield as a white solid: m.p.
212.degree.-215.degree. C.; NMR (d.sub.6 DMSO) .delta.13.0(1H,b),
7.96(2H,d), 7.04(2H,d), 6.96(2H,s), 3.90(2H,s), 3.71(3H,s), 3.65(4H,bt),
2.65(4H,bt), 2.42(6H,s); m/e 398 M+H).sup.+ ; calculated for C.sub.22
H.sub.27 N.sub.3 O.sub.4.1HBr: C, 55.2; H, 5.9; N, 8.8. found: C, 55.3; H,
5.9; N, 8.6%.
The starting material was prepared as follows:
i) In a similar manner to Example 151i), but starting from
4-chloro-2,6-lutidine there was obtained
4-4-(2,6-dimethylpyridyl)!-1-benzylpiperazine in 59% yield as a yellow
oil: NMR (CDCl.sub.3).delta.7.31(5H,m), 6.37(2H,s), 3.55(2H,s),
3.32(4H,t), 2.55(4H,t), 2.55(6H,s); m/e 282 M+H).sup.+.
ii) In a similar manner to Example 151ii) but starting from the product of
step i) above there was prepared the solid dihydrochloride. This was
dissolved in water, two equivalents of 2 molar potassium hydroxide added
and the solvent evaporated. Purification of the residue by flash
chromatography on alumina, eluting with 2% v/v methanol/dichloromethane
gave 1-(4-2,6-dimethylpyridyl)!piperazine in 51% yield as a white
crystalline solid: m.p. 123.degree.-124.degree. C.; NMR (CDCl.sub.3)
.delta.6.40(2H,s), 3.27(4H,t) 2.98(4H,t), 2.43(6H,s); m/e 198 (M+H.sup.+ ;
calculated for C.sub.11 H.sub.17 N.sub.3 ; C, 69.1; H, 9.0; N, 22.0 found:
C, 69.2; H, 9.2; N, 21.6%.
EXAMPLE 154
4-2-4-(2,6-Dimethylpyrid-4-yl)piperazin-1-yl!actyl!phenoxyacetic acid,
dihydrobromide
Following the method of Example 152, but starting from the product of
Example 153, the title compound was prepared in 78% yield as a fawn solid:
m.p. 210.degree.-212.degree. C.; NMR (d.sub.6 DMSO+d.sub.6 acetic acid)
.delta.7.99(2H,d), 7.16(2H,d), 7.08(2H,s), 5.09(2H,s), 4.87(2H,s),
4.07(4H,b), 3.52(4H,b), 2.49(6H,s); m/e 384 (M+H).sup.+ ; calculated for
C.sub.21 H.sub.25 N.sub.3 O.sub.4.2HBr.2.5H.sub.2 O: C, 42.7; H, 5.4; N,
7.1 found: C, 42.7; H, 5.1; N, 6.9%.
EXAMPLE 155
Methyl 4-1-(4-pyridyl)piperidin-4-yl!oxyphenoxyacetate
Diethylazodicarboxylate (0.47 ml) was added dropwise over 30 minutes to a
stirred mixture of 1-(4-pyridyl)-4-piperidinol (534 mg), methyl
4-hydroxyphenoxyacetate (546 mg), triphenylphosphine (787 mg) and dry THF
(30 ml) in an atmosphere of argon and cooled to 4.degree. C. After 1 hour
at 4.degree. C., the mixture was allowed to reach ambient temperature and
stirred for 48 hours. The solvent was removed by evaporation and the
residue purified by flash chromatography on silica eluting with 5% v/v
methanol/dichloromethane. Recrystallisation from ethyl acetate/hexane gave
the title compound, 532 mg, as a white solid: m.p. 74.degree.-76.degree.
C.; NMR (d.sub.6 DMSO) .delta.8.15(2H,bd), 6.89(6H,m), 4.71(2H,s),
4.50(1H,m), 3.70(2H,m), 3.69(3H,s), 3.23(2H,m), 1.96(2H,m), 1.62(2H,m);
m/e 343 (M+H).sup.+ ; calculated for C.sub.19 H.sub.22 N.sub.2 O.sub.4 :
C, 66.7; H, 6.5; N, 8.2. found: C, 66.2; H, 6.7; N, 8.2%.
EXAMPLE 156
4-1-(4-Pyridyl)piperidin-4-yl!oxyphenoxyacetic acid
Following the method of Example 2, but starting from the period product of
Example 155, the title compound was prepared in 85% yield: m.p.
288.degree.-291.degree. C.; NMR (NaOD+d.sub.6 DMSO).delta.7.97(2H,d),
6.77(4H,m), 6.69(2H,d), 4.35(1H,m), 4.19(2H,s), 3.53(2H,m), 3.08(2H,m),
1.82(2H,m), 1.49(2H,m); m/e 329 (M+H).sup.+ ; calculated for C.sub.18
H.sub.20 N.sub.2 O.sub.4 : C, 65.8; H, 6.1N, 8.5. found: C, 65.7; H, 6.3;
N, 8.4%.
EXAMPLE 157
Methyl 4-1-(4-pyridyl)piperidin-4-yl!methoxyphenoxyacetate
Following the method of Example 155, but starting from
4-(4-hydroxymethylpiperidin-1-yl)pyridine, the title compound was prepared
in 18% yield: m.p. 127.degree.-129.degree. C.; NMR (d.sub.6 DMSO)
.delta.8.12(2H,d), 6.84(4H,s), 6.81(2H,d), 4.70(2H,s), 3.96(2H,bd),
3.79(2H,d), 3.70(3H,s), 2.88(2H,dt), 2.01(1H,m), 1.82(2H,bd), 1.30(2H,m),
m/e 357 (M+H).sup.+ ; calculated for C.sub.20 H.sub.24 N.sub.2
O.sub.5.0.5H.sub.2 O: C, 65.7; H, 6.9; N, 7.7. found: C, 66.1; H, 6.9; N,
7.8%.
EXAMPLE 158
4-1-(4-Pyridyl)piperidin-4-yl!methoxyphenoxyacetic acid.
Following the method of Example 2 but starting from the product of Example
157, the title compound was prepared in 86% yield: m.p.
278.degree.-281.degree. C.; NMR (d.sub.6 DMSO+TFA).delta.8.09(2H,t),
7.08(2H,d), 6.78(4H,s), 4.50(2H,s), 4.20(2H,bd), 3.74(2H,d), 3.17(2H,bt),
2.12(1H,m), 1.91(2H,m) 1.32(2H,m), m/e 343 (M+H).sup.+ ; calculated for
C.sub.19 H.sub.22 N.sub.2 O.sub.4.0.25H.sub.2 O: C, 65.8; H, 6.5; N, 8.1.
found: C, 66.0; H, 6.6; N, 8.0%.
EXAMPLE 159
Methyl 4-2-1-(4-pyridyl)piperidin-4-yl!ethoxy!phenoxyacetate
Following the method of Example 155, but starting from
4-(4-hydroxyethylpiperidin-1-yl)pyridine, the title compound was prepared
in 65% yield: m.p. 86.degree.-88.degree. C.; NMR (d.sub.6 DMSO)
.delta.8.11(2H,d), 6.85(4H,s), 6.79(2H,d), 4.70(2H,s), 3.96(2H,t),
3.92(2H,bd), 3.69(3H,s), 2.81(2H,dt), 1.78(2H,bd), 1.73(1H,m), 1.65(2H,q),
1.20(2H,m); m/e 371 M+H).sup.+ ; calculated for C.sub.21 H.sub.26 N.sub.2
O.sub.4 : C, 68.1; H, 7.1; N, 7.6. found: C, 67.5; H, 7.3; N, 7.5%.
EXAMPLE 160
4-2-1-(4-Pyridyl)piperidin-4-yl!ethoxy!phenoxyacetic acid
Following the method of Example 2, but starting from the product of Example
159, the title compound was prepared in 74% yield; m.p.
247.degree.-249.degree. C.; NMR (d.sub.6 DMSO+TFA).delta.8.19(2H,t),
7.19(2H,d), 6.38(4H,s), 4.60(2H,s), 4.25(2H,bd), 4.01(2H,t), 3.20(2H,dt),
1.93(3H,m), 1.70(2H,q), 1.28(2H,m); m/e 357 (M+H).sup.+ ; calculated for
C.sub.20 H.sub.24 N.sub.2 O.sub.4 ; C, 67.4; H, 6.8; N, 7.9 found: C,
67.0; H, 6.8; N, 7.7%.
EXAMPLE 161
Methyl 3-4-1-(4-pyridyl)piperidin-4-yl!methoxyphenyl!propionate
Following the method of Example 155, but starting from
4-(4-hydroxymethylpiperidin-1-yl)pyridine and methyl
3-(4-hydroxyphenyl)propionate, the title compound was prepared in 14%
yield: m.p. 96.5.degree.-98.5.degree. C.; NMR (d.sub.6 DMSO)
.delta.8.13(2H,d), 7.11(2H,d), 6.83(4H,m), 3.97(2H,dm), 3.81(2H,d),
3.56(3H,s), 2.87(2H,dt), 2.77(2H,t), 2.57(2H,t), 2.01(1H,m), 1.84(2H,m),
1.30(2H,m); m/e 355 (M+H).sup.+ ; calculated for C.sub.21 H.sub.26 N.sub.2
O.sub.3.0.75H.sub.2 O: C, 68.5; H, 7.2; N, 7.8. found: C, 68.5; H, 7.5; N,
7.6%.
EXAMPLE 162
3-4-1-(4-Pyridyl)piperidin-4-yl!methoxyphenyl!propionic acid
Following the method of Example 2, but starting from the product of Example
161, the title compound was prepared in 80% yield: m.p.
303.degree.-307.degree. c.; NMR (d.sub.6 DMSO+TFA).delta.8.20(2H,d),
7.25(6H,m), 4.31(2H,m), 3.88(2H,d), 3.27(2H,bt), 2.82(2H,t), 2.52(2H,t),
2.25(1H,m), 2.00(2H,bd), 1.40(2H,m); m/e 341 (M+H).sup.+ ; calculated for
C.sub.20 H.sub.24 N.sub.2 O.sub.3.0.25H.sub.2 O: C, 69.6; H, 7.2; N, 8.1.
found: C, 69.6; H, 7.2; N, 8.0%.
EXAMPLE 163
Methyl 4-1-(4-pyridyl)piperidin-4-yl!carboxamido!phenoxyacetate,
hydrochloride
Thionyl chloride (5 ml) was added dropwise over ten minutes to a stirred
suspension of 1-(4-pyridyl)-4-piperidinecarboxylic acid (2.06 g) in dry
dichloromethane (20 ml) at 4.degree. C. After 1 hour at 4.degree. C., the
mixture was allowed to reach ambient temperature and stirred for 16 hours.
The solvent was removed by evaporation and the residue dried under high
vacuum to give a solid foam (2.84 g).
Triethylamine (0.70 ml) was added to a stirred suspension of methyl
4-aminophenoxyacetate hydrochloride (544 mg) in dry dichloromethane (10
ml). After stirring for 1 hour, the mixture was cooled to 4.degree. C.,
and the foam (0.71 g) added. After 1 hour at 4.degree. C. the mixture was
allowed to reach ambient temperature and stirred for 16 hours. The
precipitated solid was collected, washed with dichloromethane and, on
recrystallisation from water, gave the title compound, 744 mg; m.p.
233.degree.-234.5.degree. C.; NMR (d.sub.6 DMSO).delta.13.56(1H,b),
9.98(1H,s), 8.21(2H,d), 7.51(2H,d), 7.20(2H,d), 6.85(2H,d), 4.72(2H,s),
4.25(2H,bd), 3.69(3H,s), 3.72(2H+H.sub.2 O), 2.78(1H,m), 1.97(2H,m),
1.67(2H,m); m/e 370 (M+H).sup.+ ; calculated for C.sub.20 H.sub.23 N.sub.3
O.sub.4.HCl: C, 59.2; H, 6.0; N, 10.4. found: C, 58.8; H, 6.1; N, 10.3%
EXAMPLE 164
4-4-1-4-Pyridyl)piperidin-4-yl!carboxamido!phenoxyacetic acid
Following the method of Example 2, but starting from the product of Example
163, the title compound was prepared in 69% yield: m.p.
285.degree.-287.degree. C.; NMR (NaOD).delta.8.30(2H,d), 7.44(2H,d),
7.07(2H,d), 7.04(2H,d), 4.60(2H,s), 4.14(2H,bd), 3.11(2H,dt), 2.81(1H,m),
2.11(2H,bd), 1.88(2H,dq); m/e 356 (M+H).sup.+ ; calculated for C.sub.19
H.sub.21 N.sub.3 O.sub.4.H.sub.2 O: C, 61.1; H, 6.2; N, 11.3. found: C,
60.9; H, 6.2; N, 11.0%.
EXAMPLE 165
Methyl 4-2-(1-(4-pyridyl)piperidin-4-yl!acetamido!phenoxyacetate
To a stirred solution of 1-(4-pyridylpiperdin-4-yl)acetic acid
hydrochloride (400 mg) in dry DMF (5 ml) was added
N,N'-diisopropylethylamine (1.1 ml), HOBT (240 mg),
2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyuronium hexafluorophosphate
(600 mg). After 15 minutes methyl 4-aminophenoxyacetate (280 mg) was added
and stirring contiuned overnight. The reaction mixture was added to ethyl
acetate (100 ml) and this mixture washd with water, 10% w/v sodium
hydrogen sulphate solution and brine, then dried (MgSO.sub.4) and
evaporated. Purification of the resulting gum by flash chromatography,
first on silica eluting with 0 to 5% v/v methanol/dichloromethane and then
on neutral alumina eluting with 2% v/v methanol/dichloromethane gave, on
trituration with diethyl ether the title compound, 55 mg, as an off-white
solid: m.p. 155.degree.-157.degree. C.; NMR (d.sub.6 DMSO)
.delta.9.74(1H,s), 8.11(2H,d), 7.48(2H,d), 6.86(2H,d), 6.79(2H,d),
4.73(2H,s), 3.91(2H,bd), 3.70(3H,s), 2.84(2H,dt), 2.21(2H,d), 2.03(1H,m),
1.72(2H,bd), 1.22 (2H,dq); m/e 384(M+H).sup.+ ; calculated for C.sub.21
H.sub.25 N.sub.3 O.sub.4. 0.5 H.sub.2 O: C, 64.5; H, 6.6; N, 10.7. found:
C, 64.7; H, 6.8; N, 10.8%.
The starting material was prepared as follows:
i) A mixture of ethyl 4-carboxymethylpiperidine (from Example 29ii) (3.25
g), triethylamine (5.28 ml), 4-chloropyridine hydrochloride (2.85 g) and
xylene (100 ml) was heated at reflux temperature overnight. The mixture
was cooled, the precipitate removed by filtration and the filtrate
evaporated. A solution of the residue in dichloromethane was washed with
water, then dried (MgSO.sub.4) and evaporated. Purification by flash
chromatography on silica, eluting with 10% v/v methanol/dichloromethane,
gave ethyl 1-(4-pyridylpiperdin-4-yl)acetate, 2.15 g, as an oil: NMR
(CDCl.sub.3).delta.8.23(2H,d), 6.64(2H,d), 4.26(2H,q), 3.88(2H,dm),
2.89(2H,dt), 2.27(2H,d), 2.05(1H,m), 1.82(2H,dm), 1.36(2H,dq), 1.27(3H,t);
m/e 249(M+H).sup.+.
ii) A mixture of the product from step i) (2.20 g), 1 molar hydrochloric
acid (35.5 ml) and dixoane (100 ml) was heated at 95.degree. C. for 3
hours. The resulting solution, on freeze-drying, gave
1-(4-pyridylpiperidin-4-yl)acetic acid hydrochloride, 2.3 g, as a
light-brown powder: m.p. 105.degree.-108.degree. C.; NMR (d.sub.6 DMSO)
.delta.13.57(1H,b), 8.18(2H,d), 7.17(2H,d), 4.21(2H,bd), 3.17(2H,dt),
2.21(2H,d), 2.09(1H,m), 1.83(2H,dm); 1.22(2H,dq); m/e 221(M+H).sup.+ ;
calculated for C.sub.12 H.sub.16 N.sub.2 O.sub.2.HCl. 1.25 H.sub.2 O: C,
51.6; H, 7.0; N, 10.0; Cl, 12.7. found C, 51.7; H, 7.0; N,9.8; Cl, 12.2%.
EXAMPLE 166
4-2-1-(4-Pyridyl)piperidin-4-yl!acetamido!phenoxyacetic acid
dihydrochloride
A mixture of the product from Example 165 (30 mg), 1 molar hydrochlori acid
(0.40 ml), water (2 ml) and dioxane (1 ml) was heated at 95.degree. C. for
1 hour. The resulting solution, on freeze-drying and trituration of the
residue with ether, gave the title compound, 25 mg, as a light brown
solid: m.p. 158.degree.-162.degree. C.; NMR (d.sup.6 DMSO+d.sup.4 acetic
acid) 8.17(2H,d), 7.49(2H,d), 7.20(2H,d), 6.85(2H,d), 4.61(2H,s),
4.23(2H,bd), 3.21(2H,bt), 2.21(3H,m); 1.86(2H,bd+acetic acid),
1.28(2H,bq); m/e 370(M+H).sup.+ ; calculated for C.sub.20 H.sub.23 N.sub.3
O.sub.4. 2HCl. 1.25 H.sub.2 O: C, 51.7; H, 5.9; N, 6.0. found: C, 51.6; H,
6.0; N, 9.2%.
EXAMPLE 167
4-1-(4-Pyridyl)piperidin-4-yl!aminocarbonyl!phenoxyacetic acid
dihydrochloride
Following the method of Example 166, but starting from tertiary butyl
4-1-(4-pyridyl)piperidin-4-yl!aminocarbonyl!phenoxyacetate (50 mg), but
with the removal of the insoluble precipitate before freeze-drying, the
title compound was prepared in 50% yield: m.p. 278.degree.-280.degree. C.;
NMR (d.sub.6 DMSO+d.sub.4 acetic acid) .delta.8.19(2H,d), 7.82(2H,d),
7.20(2H,d), 6.98(2H,d), 4.74(2H,s), 4.23(3H,m), 3.38(2H,bt), 2.04(2H,m),
1.64(2H,m); m/e 356 (M+H).sup.+ ; calculated for C.sub.19 H.sub.21 N.sub.3
O.sub.4.2HCl. 1.25 H.sub.2 O: C, 50.6; H, 5.7; N, 9.3. found: C, 50.6; H,
5.7; N, 9.2%.
The starting material were prepared as follows:
i) Acetyl chloride (3.95 ml) was added dropwise to a stirred solution of
4-aminol-benzylpiperidine (10.0 g) and triethylamine (7.7 ml) in dry
dichloromethane (100 ml) at 4.degree. C. The mixture was allowed to reach
ambient temperature and stirred for 16 hours. Water was then added, the
organic phase separated and dried (MgSO.sub.4), and removal of the solvent
by evaporation gave 4-acetylamino-1-benzylpiperidine, 10.23 g, as a light
brown solid which was used without further purification: NMR (CDCl.sub.3)
.delta.7.29)5H,m), 5.29(1H,b), 3.79(1H,m), 3.49(2H,s), 2.80(2H,dm),
2.12(2H,dt), 1.95(3H,s), 1.91(2H,dm), 1.46(2H,dq); m/e 233 (m+H).sup.+.
ii) 10% w/w Palladium on charcoal (1.5 g) was added to a solution of the
product from step i) (10.0 g), 1 molar hydrochloric acid (21.5 ml) and
methanol (150 ml) and the mixture hydrogenated at room temperature and
pressure until the theoretical amount of hydrogen had been taken up.
Charcoal was added, the mixture stirred for 1 hour then filtered through
diatomaceous earth and the filtrate evaporated to dryness giving
4-acetylaminopiperidine hydrochloride, 8.64 g, as a sticky foam; NMR
(CDCl.sub.3 +d.sub.6 DMSO) .delta.9.72(1H,b), 9.02(1H,b), 7.40(1H,bd),
3.87(1H,m), 3.30(2H,m), 2.81(2H,m), 1.86(4H,m), 1.80(3H,s); m/e 143
(M+H).sup.+.
iii) A mixture of the product from step ii) (1.79 g), 4-chloropyridine
hydrochloride (1.50 g), sodium hydrogen carbonate (2.86 g) in 3-methyl
1-butanol (25 ml) was heated at reflux temperature for 16 hours. The
cooled mixture was filtered and the filtrate concentrated in vacuo.
Purification of the residue by flash chromatography on silica, eluting
with methanol/dichloromethane (1:2 v/v) gave
4-acetylamino-1-(4-pyridyl)piperidine as a foam, 0.69 g: NMR (d.sub.6
DMSO) .delta.8.10(2H,d), 7.80(1H,bd), 6.80(2H,dd), 3.82(3H,m),
2.93(2H,dt), 1.78(3H,s), 1.77(2H,m), 1.33(2H;dq); m/e 220 (M+H).sup.+.
iv) The product from step iii) (0.52 g) in 1 molar hydrochloriac acid (11.9
ml) was heated at 95.degree. C. for 5 hours. The solvent was evaporated
and the residue, on drying over potassium hydroxide in vacuo gave
4-amino-1-(4-pyridyl)piperidine trihydrochloride hydrate, 0.70 g as a
light brown solid: m.p. >300.degree. C; NMR (d.sub.6 DMSO)
.delta.8.28(4H,m), 7.22(2H,d) 4.27(2H,bd), 3.5 to 3.15(3H+H.sub.2 O),
2.09(2H,m), 1.59(2H,dq); m/e 178(M+H).sup.+ ; calculated for C.sub.10
H.sub.15 N.sub.3. 3HCl.0.75 H.sub.2 O: C, 40.0; H, 6.5; N, 14.0. found: C,
40.4; H, 6.3; N, 13.5%.
v) A mixture of benzyl 4-hydroxybenzoate (4 g), t-butyl bromoacetate (3.7),
powdered anhydrous potassium carbonate (2.4 g) and acetone (100 ml) was
heated at reflux for 3 days. The reaction mixture was cooled and then
filtered and the filtrate evaporated to dryness to give a viscous oil
(6.37 g). A portion of this oil (3.4 g) was dissolved in methanol (30 ml)
and ammonium formate (4 g) was added. The resultant solution was covered
with a blanket of argon before a slurry of 10% Pd on C (100 mg) in
methanol (5 ml), also under argon, was added. The reaction mixture was
stirred at room temperature for 18 hours then the catalyst was filtered
off through a pad of kieselguhr and washed with ethanol and water. The
combined filtrate and washings were evaporated to dryness and the residue
was partitioned between dichloromethane and aqueous sodium bicarbonate.
The aqueous layer was separated, washed with dichloromethane and then
carefully acidified with dilute aqueous citric acid solution. A solid
precipitated which was collected, washed with water and air-dried to give
4-t-butoxycarbonylmethoxybenzoic acid (1.45 g), as a white crystalline
solid: m.p. 119.degree.-121.degree. C.
vi) Following the method of Example 165, but starting from the product of
step v) and the product from step iv) and purification by flash
chromatography on silica eluting with 0-5% v/v methanol/dichloromethane
there was obtained tertiary butyl
4-1-(4-pyridyl)piperidin-4-yl!aminocarbonyl!phenoxyacetate
hexafluorophosphate in 49% yield as a white solid: m.p.
196.degree.-198.degree. C.; NMR (d.sub.6 DMSO) .delta.8.21(2H,d),
8.18(1H,d), 7.80(2H,d), 7.19(2H,d), 6.95(2H,d), 4.72(2H,s), 4.20(3H,m),
3.5-3.1(4H+H.sub.2 O), 1.98(2H,m), 1.59(2H,m), 1.42(9H,s); m/e 412
(M+H).sup.+ ; calculated for C.sub.23 H.sub.29 N.sub.3 O.sub.4. HPF.sub.6
: C, 4.96; H, 5.4; N, 7.5, found: C, 49.1; H, 5.5; N, 7.3%. The free base
was generated by flash chromatography on neutral alumina eluting with 1%
v/v methanol dichloromethane and used in the preparation of the acid.
EXAMPLE 168
4-1-(4-Pyridyl)piperidin-4-yl!methylaminocarbonylphenoxyacetic acid
Following the method of Example 166, but starting from tert-butyl
4-1-(4-pyridyl)piperidin-4-yl!methylaminocarbonyl!phenoxyacetate, the
title compound was prepared in 95% yield: m.p. 84.degree.-86.degree. C.;
NMR (d.sub.6 DMSO) .delta.8.38(1H,t), 8.18(2H,d), 7.81(2H,d), 7.19(2H,d),
6.95(2H,d), 4.73(2H,s), 4.20(2H,bd), 3.8-3.0(H.sub.2 O), 1.99(1H,m),
1.84(2H,bd), 1.21(2H,m); m/e 370 (M+H).sup.+.
The starting material was prepared as follows:
Following the method of Example 167i), but starting from
1-tert-butyloxycarbonylpiperidin-4-ylmethylamine tosylate there was
prepared N-(1-tertiarybutyloxycarbonylpiperidine-4yl)methyl!acetamide in
95% yield as an oil which slowly crystallised: NMR (CDCl.sub.3)
.delta.5.52(1H,b), 4.12(2H,bd), 3,14(2H,m), 2.68(2H,dt), 1.98(3H,s),
1.67(3H,m), 1.44(9H,s), 1.12(2H,dq); m/e 257 (M+H).sup.+.
The product was used in step ii) without further purification.
ii) A solution of the product from step i) (6.50 g) in trifluoroacetic acid
(50 ml) was stirred overnight. The solvent was evaporated and the residue,
on purification by flash chromatography on neutral alumina, eluting with
10% v/v methanol/dichloromethane gave N-4-piperidinylmethyl!acetamide,
3.78 g, as a yellow oil: NMR (d.sup.4 acetic acid) .delta.3.22(2H,bd),
2.96(2H,d), 2.81(2H,dt), 1.83(3H,s), 1.76(2H,bd), 1.67(1H,m), 1.26(2H,dq);
m/e 157 (M+H).sup.+.
iii) Following the method of Example 165), but starting from the product of
ii) above and purification by flash chromatography on silica eluting with
20 to 33% v/v methanol/dichloromethane there was obtained
4-(4-acetylaminomethylpiperidin-1-yl)pyridine in 28% yield as a gummy
solid: NMR (d.sub.6 DMSO) .delta.8.18(2H,d), 7.90(1H,t), 7.07(2H,d),
4.12(2H,bd), 3.05(2H,dt), 2.95(2H,t), 1.80(3H,s), 1.77(3H,m), 1.13(2H,m);
m/e 234 (M+H).sup.+.
iv) Following the method of Example 167iv), but starting from the product
of iii) above, there was obtained 4-(4-aminomethylpiperidin-1-yl)pyridine
in 95% yield as a yellow gum: NMR (d.sub.6 DMSO) .delta.8.26(4H,m),
7.21(2H,d), 4.26(2H,bd), 3.19(2H,dt), 2.74(2H,t), 2.05(1H,m), 1.92(2H,bd),
1.26(2H;dq); m/e 192 (M+H).sup.+.
v) Following the method of Example 165, but starting from the product of
Example 167v) and the product from step iv) above and purification by
flash chromatography on silica, eluting with 0 to 5% v/v
methanol/dichloromethane and trituration with diethyl ether there was
obtained tertiary butyl
4-1-(4-pyridyl)piperidin-4-yl)!methylaminocarbonyl!-phenoxyacetate
hexafluorophosphate in 35% yield as a white solid: m.p.
182.degree.-184.degree. C.; NMR (d.sub.6 DMSO) .delta.13.11(1H,b),
8.37(1H,t), 8.17(2H,d), 7.80(2H,d), 7.19(2H,d), 6.95(2H,d), 4.72(3H,s),
4.21(2H,bd), 3.19(4H,m), 2.00(1H,m), 1.86(2H,m), 1.43(9H,s), 1.21(2H,m);
m/e 426(M+H).sup.+ ; calculated for C.sub.24 H.sub.31 N.sub.3
O.sub.4.HPF.sub.6.0.5 H.sub.2 O; C, 49.6; H, 5.7; N, 7.2; P, 5.4. found:
C, 49.6; H, 5.7; N, 7.1; P, 5.8%.
EXAMPLE 169
4-1-(4-Pyridyl)piperidine-4-yl!carboxyamido!acetic acid
Following the method of Example 2, but starting from methyl
4-1-(4-pyridyl)piperidin-4-yl!carboxamido!phenylacetate hydrochloride
the title compound was prepared in 93% yield: m.p. 281.degree.-282.degree.
C.; NMR (d.sub.6 DMSO) .delta.9.87(1H,s), 8.13(2H,d), 7.51(2H,d),
7.16(2H,d), 6.83(2H,dd), 4.00(2H,dm), 3.49(2H,s), 2.90(2H,dt), 2.61(1H,m),
1.87(2H,dd), 1.66(2H,dq); m/e 340 (M+H).sup.+ ; calculated for C.sub.19
H.sub.21 N.sub.3 O.sub.3 : C, 67.2; H, 6.2; N, 12.4. found: C, 67.4; H,
6.2; N, 12.4%.
The starting material was prepared as follows:
i) Following the method of Example 163, but starting from methyl
4-aminophenylacetate hydrochloride, methyl
4-1-(4-pyridyl)piperidin-4-yl!carboxamido!-phenylacetate hydrochloride
was prepared in 78% yield: m.p. 235.degree.-236.5.degree. C.; NMR (d.sub.6
DMSO) .delta.13.61(1H,b), 10.10(1H,s) 8.21(2H,d), 7.55(2H,d), 7.21(2H,d),
7.16(2H,d), 4.28(2H,dm), 3.60(5H,s), 3.30(2H,m+H.sub.2 O), 2.81(1H,m),
1.98(2H,m), 1.67(2H;m); m/e 354(M+H).sup.+ ; calculated for C.sub.20
H.sub.23 N.sub.3 O.sub.3. HCl: C, 61.6; H, 6.2; N, 10.8. found: C, 61.7;
H, 6.3; N, 10.6%.
EXAMPLE 170
N-4-4-1-(4-Pyridyl)piperidin-4-yl!carboxamidophenyl!-methyl!-1-butanesul
phonamide
4-1-(4-Pyridyl)piperidin-4-ylcarboxamido!benzylamine dihydrochloride,
hydrate (1.09 g) was dissolved in water and treated with 1 molar sodium
hydroxide and the mixture stirred for 3 hours. The solid precipitate was
collected, washed with water and dried to give
4-1-(4-pyridyl)piperidin-4-ylcarboxamido!benzylamine (840 mg).
1-Butanesulphonyl chloride (0.08 ml) was added to a stirred solution under
argon of the amine (160 mg) and triethylamine (0.09 ml) in dry DMF at
4.degree. C. After 2 hours, the solvent was evaporated in vacuo. The
residue was dissolved in water, 1 molar sodium hydroxide added and the
precipiate collected and dried. Purification of this solid by flash
chromatography on silica, eluting with 15% v/v methanol/dichloromethane
and recrystallisation from methanol gave the title compound, 146 mg: m.p.
98.degree.-101.degree. C. NMR (d.sub.6 DMSO) .delta.9.90(1H,s),
8.24(2H,d), 7.56(2H,d), 7.50(1H,t), 7.24(2H,d), 6.82(2H,d), 4.06(2H,d),
3.99(2H,dm), 2.89(4H,m), 2.61(1H,m), 1.85(2H,dd), 1.62(4H,m), 1.30 (2H,m),
0.82(3H,t); m/e 431 (M+H).sup.+ ; calculated for C.sub.22 H.sub.30 N.sub.4
O.sub.3 S.H.sub.2 O: C, 58.9; H, 7.2; N, 12.5. found: C, 58.5; H, 7.3; N,
12.3%.
The starting material was prepared as follows:
i) A mixture of 4-nitrobenzylamine hydrochloride (5.00 g), triethylamine
(25 ml), dry DMF (25 ml) and di-tertiary-butyl dicarbonate (6.07 g) was
stirred for 16 hours then the solvent was evaporated in vacuo. The residue
was partitioned between ethyl acetate (200 ml) and water (50 ml),
separated and the organic phase washed successively with water, 0.5 molar
sodium hyroxide, water and brine, dried (MgSO.sub.4) and evaporated.
Recrystallisation of the solid residue from ethyl acetate/hexane gave
N-tertiary-butyloxycarbonyl-4-nitrobenzylamine, 5.65 g: m.p.
110.degree.-111.degree. C.; NMR (d.sub.6 DMSO) .delta.8.19(2H,d),
7.52(1H,bt), 7.51(2H,d), 4.24(2H,d), 1.40(9H,s); m/e 253(M+H).sup.+ ;
calculated for C.sub.12 H.sub.16 N.sub.2 O.sub.4 : C, 57.1; H, 6.4; N,
11.1. found: C, 56.9; H, 6.3; N, 10.9%.
ii) 10% w/w palladium on charcoal (250 mg) was added to a solution of the
product from step i) (5.37 g) in ethanol (100 ml) and the mixture
hydrogenated at room temperature and pressure until the theoretical amount
of hydrogen had been taken up. Charcoal was added, the mixture stirred for
10 minutes then filtered through diatomaceous earth and the filtrate
evaporated to dryness. The solid residue, on recrystallisation from ethyl
acetate/hexane gave 4-(N-tertiary-butyloxycarbonylaminomethyl)aniline,
4.20 g; m.p. 80.degree.-82.degree. C.; NMR (d.sub.6 DMSO)
.delta.7.10(1H,bt), 6.88(2H,d), 6.49(2H,d), 4.92(2H,s), 3.92(2H,d),
1.38(9H,s); m/e 223(M+H).sup.+ ; calculated for C.sub.12 H.sub.18 N.sub.2
O.sub.2 : C, 64.8; H, 8.2; N, 12.6. found: C, 65.4; H, 8.3; N, 13.0%.
iii) Thionyl chloride (5 ml) was added dropwise over ten minutes to a
stirred suspension of 1-(4-pyridyl)-4-piperidinecarboxylic acid (5.15 g)
in dry dichloromethane (20 ml) at 4.degree. C. After 1 hour at 4.degree.
C., the mixture was allowed to reach ambient temperature and stirred for
16 hours. The solvent was removed by evaporation and the residue dried
under high vacuum to give a solid foam (7.06 g). The foam (4.31 g) was
added, under argon, to a stirred solution of the product from step (ii)
(3.55 g) and triethylamine (4.59 ml) in dry dichloromethane (150 ml) at
4.degree. C. After 1 hour at 4.degree. C., the mixture was allowed to
reach ambient temperature and stirred for 16 hours. Dichloromethane (150
ml) was added and the mixture washed with water (3.times.30 ml), dried
(MgSO.sub.4) and evaporated. The solid residue on recrystallisation from
ethyl acetate gave
N-tertiary-butyloxycarbonyl-4-1-(4-(pyridyl)piperidin-4-ylcarboxamido!-be
nzylamine, 4.22 g: m.p. 215.degree.-217.degree. C. NMR (d.sub.6 DMSO)
.delta.9.88(1H,s), 8.15(2H,d), 7.52(2H,d), 7.30(1H,t) 7.14(2H,d),
6.82(2H,d), 4.02(4H,m), 2.90(2H,dt), 2.61(1H,m), 1.87(2H,dd), 1.65(2H,dq);
m/e 411 (M+H).sup.+ ; calculated for C.sub.23 H.sub.30 N.sub.4 O.sub.3 :
C, 67.2; H, 7.4; N, 13.6. found: C, 67.3; H, 7.4; N, 13.5%.
iv) A hydrogen chloride solution in dry ether (40 ml) was added to a
stirred suspension of the product of step iii) (4.10 g) in acetonitrile
(100 ml) under argon. After 2.5 hours, the solid was collected, washed
with dry ether and dried over potassium hydroxide to give
4-1-(4-pyridyl)piperidin-4-ylcarboxamido!benzylamine dihydrochloride,
3.78 g, as a white solid: m.p. 286.degree.-289.degree. C.; NMR (d.sub.6
DMSO) .delta.13.69(1H,b), 9.96(1H,s), 8.39(3H,b), 8.23(2H,d), 7.66(2H,d),
7.40(2H,d), 7.22(2H,d), 4.27(2H,bd), 3.93(2H,m), 3.26(2H,m), 2.86(1H,m),
2.00(2H,bd), 1.69(2H,bq); m/e 311 (M+H).sup.+ ; calculated for C.sub.18
H.sub.22 N.sub.4 O.2HCl.0.5 H.sub.2 O: C 55.1; H, 6.4; N, 14.3. found. C,
54.9; H, 6.4; N, 13.9%.
EXAMPLE 171
N-44-1-(4-Pyridyl)piperidin-4yl!carboxyamidophenyl!methyl!-4-methylpheny
lsulphonamide
4-Methylphenylsulphonyl chloride (419 mg) was added to a stirred mixture of
the product of Example 170 step (iv) (766 mg), triethylamine (0.86 ml) and
dry DMF (15 ml) at 4.degree. C. After 1 hours, the mixture was allowed to
attain ambient temperature and stirred for 16 hours. Then further
4-methylphenylsulphonyl chloride (210 mg) and triethylamine (0.17 ml) were
added and stirring continued for 24 hours. The precipitated solid was
collected, washed with dichloromethane and water. This solid was suspended
in 1 molar sodium hydroxide, the mixture stirred for 3 hours. The solid
was collected, washed well with water and on drying, gave the titled
compound, 734 mg: m.p. 124.degree.-127.degree. C.; NMR (d.sub.6 DMSO)
.delta.9.37(1H,s), 8.15(2H,b), 7.94(1H,t), 7.67(2H,d), 7.48(2H,d),
7.36(2H,d), 6.32(2H, bd), 3.99(2H,bd), 3.87(2H,d), 2.90(2H,bt),
2.58(1H,m), 2.48(3H,s), 1.84(2H,bd), 1.63(2H,dq); m/e 465 (M+H).sup.+ ;
calculated for C.sub.25 H.sub.28 N.sub.4 O.sub.3 S. 1.25 H.sub.2 O: C,
61.6; H, 6.3; N, 11.5; S, 6.6. found: C, 61.5; H, 6.1; N, 11.2; S, 7.0%.
EXAMPLE 172
4-Methyloxycarbonylmethylamiophenyl 1-(4-pyridyl)piperidin4-yl!acetate
Thionyl chloride (1 ml) was added dropwise to a stirred suspension of
1-(4-pyridyl)piperidin-4-yl!acetic acid (300 mg) in dry dichloromethane
(5 ml) and the mixture stirred for 4 hours. The solvent was evaporated and
the residue triturated with hexane and dried under high vacuum over
potassium hydroxide to give a solid foam. A solution of the foam in dry
dichloromethane (5 ml) was added dropwise to a stirred solution of methyl
N-(4-hydroxyphenyl)glycinate (210 mg) and triethylamine (0.33 ml) in dry
dichloromethane (10 ml) and the mixture stirred for 16 hours. The mixture
was diluted with dichloromethane, washed with water, dried and evaporated.
Purification by flash chromatography on silica, eluting with 0-10% v/v
methanol/dichloromethane and trituration of the resulting gum with diethyl
ether gave the title compound, 80 mg, as a white solid: m.p.
120.degree.-122.degree. C.; NMR (d.sub.6 DMSO) .delta.8.13(2H,d),
6.84(2H,d), 6.81(2H,d) 6.54(2H,d), 6.01(1H,t), 3.96(2H,bd), 3.90(2H,d),
3.66(3H,s), 2.90(2H,dt), 2.50(2H,d+DMSO), 2.07(1H,m), 1.81(2H,bd),
1.30(2H,dq); m/e 384(M+H).sup.+ ; calculated for C.sub.21 H.sub.25 N.sub.3
O.sub.4. 0.5 H.sub.2 O: C, 64.3; H, 6.6; N, 10.7. found: C, 64.2; H, 6.3;
N, 10.7%.
EXAMPLE 173
Methyl 4-2-1-(4-pyridyl)piperidin-4-yl!acetyl!phenoxyacetate
Oxalyl chloride (2.40 ml) was added to a stirred suspension of
1-(4-pyridyl)piperidin-4-yl!acetic acid acid hydrochloride hydrate (1.25
g) in dry dichloromethane under argon. A few drops of dry DMF were added
and the mixture stirred for 30 minutes to give a clear solution. The
solvent was removed in vacuo and the residue dried. The resulting solid
foam was suspended in dichloroethane (40 ml), the suspension cooled to
4.degree. C. and with stirring, aluminium chloride (3.21 g) added. After
30 minutes the mixture was allowed to warm to ambient temperature when
methyl phenoxyacetate (1.16 ml) was added and stirring continued for a
further 2.5 hours. The mixture was added to an ice-water mixture to which
was added dichloromethane. The aqueous phase was adjusted to pH7 and the
solid removed by filtration. The filtrate was extracted three times with
dichloromethane and the extracts dried (MgSO.sub.4). Evaporation of the
solvent gave a clear oil which crystallised on addition of ether. The
solid was collected and on recrystallisation from methyl acetate gave the
title compound, 1.06 g: m.p. 137.degree.-138.degree. C.; NMR (d.sub.6
DMSO) .delta.8.11(2H,b), 7.94(2H,d), 7.03(2H,d), 6.78(2H,bd), 4.91(2H,s),
3.90(2H,d), 3.71(3H,s), 2.91(2H,d), 2.85(2H,dt), 2.12(1H,m), 1.75(2H,bd),
1.26(2H,dq); m/e 369 (M+H).sup.+ ; calculated for C.sub.21 H.sub.24
N.sub.2 O.sub.4 : C, 68.5; H, 6.6; N, 7.6. found C, 68.2; H, 6.5; N, 7.5%.
The starting 1-(4-pyridyl)piperidin-4-yl!acetic acid hydrochloride hydrate
is described in Example 165i) and ii).
EXAMPLE 174
4-2-1-(4Pyridyl)piperidin-4-yl!acetyl!phenoxyacetic acid hydrochloride
A mixture of the product of Example 173 (300 mg), dioxan (10 ml) and 1
molar hydrochloric acid (2.7 ml) were stirred for 80 hours at ambient
temperature. The solvent was removed in vacuo and a little water added.
The resulting solid was collected, washed with water and, after drying,
gave the titled compound, 170 mg; m.p. 239.degree.-241.degree. C.; NMR
(D.sub.2 O) .delta.8.17(2H,d), 8.15(2H,d), 7.36(2H,d), 7.20(2H,d),
5.01(2H,s), 4.33(2H,d), 3.38(2H,dt), 3.16(2H,d) 2.48(1H,m), 2.08(2H,d),
1.54(2H,dq); m/e 355 (M+H).sup.+ ; calculated for C.sub.20 H.sub.22
N.sub.2 O.sub.4.HCl.1.5H.sub.2 O; C, 57.4; H, 6.1; N, 6.7. found: C, 57.3;
H, 6.1; N, 6.4%.
EXAMPLE 175
Methyl 4-2-4-(4-pyridyl)piperazin-1yl!-2,2-dimethylacetyl!-phenoxyacetate
Methyl 4-(2,2-dimethylbromoacetyl)phenoxyacetate (1.58 g) was added to a
stirred solution of 1-(4-pyridyl)piperazine (1.63 g) in acetonitrile (40
ml). After 34 days, the solid formed was removed by filtration and the
filtrate evaporated to give an oil. Purification by flash chromatography
on silica, eluting with 0.5 to 4.0% v/v methanol/dichloromethane gave the
title compound, 240 mg, as a white foam: NMR (d.sub.6 DMSO)
.delta.8.49(2H,d), 8.12(2H,d), 6.96(2H,d), 6.77(2H,d), 4.87(2H,s),
3.69(3H,s), 3.28(4H,t), 2.58(4H,t), 1.25(6H,s); m/e 398 (M+H).sup.+ ;
calculated for C.sub.22 H.sub.27 N.sub.3 O.sub.4. 0.25H.sub.2 O; C, 65.7;
H, 6.8; N, 10.4. found: C, 65.3; H, 6.9; N, 10.4%.
The starting material was prepared as follows:
i) Following the method of Example 118i) but starting from
4-2,2-dimethylacetyl)phenol and only stirring for 18 hours instead of 2
days, there was obtained methyl 4-(2,2-dimethylacetyl)phenoxyacetate, in
90% yield, as an off-white crystalline solid: m.p. 45.degree.-46.degree.
C., NMR (d.sub.6 DMSO) .delta.7.92(2H,d), 7.02(2H,d), 4.90(2H,s),
3.71(3H,s), 3.60(1H,m), 1.09(6H,d).
ii) Bromine (2.09 ml) was added dropwise over ten minutes to a stirred
solution of the product of step i) above (9.44 g) in carbon tetrachloride
(200 ml). The solution was stirred for 16 hours, then the solvent was
evaporated in vacuo to give an orange oil. A solution of this oil, in a
small volume of dichloromethane, was filtered through silica and the clear
filtrate, on evaporation, gave methyl
4-(2-bromo-2,2-dimethylacetyl)phenoxyacetate, 11.3 g, as a white
crystalline solid: m.p. 46.degree.-50.degree. C.; NMR (d.sub.6 DMSO)
.delta.8.09(2H,d), 7.05(2H,d), 4.92(2H,s), 3.72(3H,s), 2.00(6H,s).
EXAMPLE 176
4-2-4-(4-Pyridyl)piperazin-1-yl!-2,2-dimethylacetyl!phenoxyacetic acid
Following the method of Example 2 but starting from the product of Example
175 and stirring for 16 hours instead of 2 hours, the title compound was
obtained in 76% yield, as a white crystalline solid: m.p.
278.degree.-279.degree. C.; NMR (D.sub.2 O) .delta.8.72(2H,d), 8.20(2H,d),
7.16(4H,d), 4.76(2H,s), 3.80(4H,bt), 2.91(4H,bt), 1.55(6H;s); m/e 406
(M+Na).sup.+, 384 (M+H).sup.+ ; calculated for C.sub.21 H.sub.25 N.sub.3
O.sub.4. 0.5NaCl: C, 61.1; H, 6.1; N, 10.2. found: C, 60.8; H, 5.9; N,
10.0%.
EXAMPLE 177
RS Methyl
4-3-4-(4-pyridyl)piperazin-1-yl!-2-methylpropanoyl!-phenoxyacetate
A stirred mixture of methyl 4-(2,2-dimethylbromoacetyl)phenoxyacetate (3.15
g), and 1-(4-pyridyl)piperazine (3.26 g) in acetonitrile (200 ml) was
heated at reflux temperature for 4 days. The solvent was removed in vacuo
and the residue partioned between dichloromethane/water. The organic phase
was dried (MgSO.sub.4), evaporated and then purified by flash
chromatography on silicon, eluting with 2 to 5% v/v
methanol/dichloromethane. Further purification by flash chromatography on
neutral alumina, eluting with dichloromethane, gave the title compound,
350 mg, as a clear oil: NMR (d.sub.6 DMSO) .delta.8.12(2H,d), 7.98(2H,d),
7.04(2H,d), 6.75(2H,d), 4.92(2H,s), 3.86(1H,m), 3.71(3H,s), 3.19(4H,t),
2.70(1H,q), 2.49(DMSO+4H), 2.36(1H,q), 1.09(3H,s), trace of
dichloromethane; m/e 398 (M+H).sup.+ ; calculated for C.sub.22 H.sub.27
N.sub.3 O.sub.4 0.1 CH.sub.2 Cl.sub.2 : C, 65.3; H, 6.7; N, 10.3. found:
C, 65.1; H, 6.9; N, 10.1%.
EXAMPLE 178
Methyl 4-4-4-(4-pyridyl)piperazin-1-yl!methylphenyl!butyrate
1-(4-Pyridyl)piperazine (1.63 g) was dissolved in warm acetontrile (25 ml),
the solution cooled to 30.degree. C. and with stirring, a solution of
methyl 4-(4-bromomethylphenyl)butyrate in acetonitrile (5 ml) added. After
30 minutes the resulting precipitate was removed by filtration and the
filtrate concentrated in vacuo to give a yellow oil. Purification by flash
chromatography on silica, eluting with 0 to 4% v/v
methanol/dichloromethane gave a solid. Trituration with ether and removal
of the insoluble solid gave a clear solution. Concentration of this
solution gave the title compound, 0.90 g, as a white fluffy solid: m.p.
126.degree.-127.degree. C.; NMR (d.sub.6 DMSO) .delta.8.14(2H,d),
7.24(2H,d), 7.14(2H,d), 6.77(2H,d), 3.59(3H,s), 3.48(2H,s), 3.30(4H,t),
2.59(2H,t), 2.47(4H,t), 2.32(2H,t), 1.63(2H,m); m/e 354 (M+H).sup.+ ;
calculated for C.sub.21 H.sub.27 N.sub.3 O.sub.2 0.25H.sub.2 O: C, 70.4;
H, 7.7; N, 11.7. found: C, 70.6; H, 7.6; N, 11.7%.
EXAMPLE 179
Methyl 5-4-4-(4-pyridyl)piperazin-1-yl!methylphenyl!pentanoate
A mixture a methyl 5-(4-bromomethylphenyl)pentanoate and
5-(2-bromometylphenyl)pentanoate, 70:30 w/w by NMR, prepared according to
the method for the starting material in Example 178 (2.14 g) was reacted
in a similar manner to Example 178. The crude mixture of esters was
purified by flash chromatography on silica, eluting with 0-5% v/v
methanol/dichloromethane. Evaporation of the appropriate fractions gave
the title compound, 605 mg, as a waxy solid: m.p. 53.degree.-54.degree.
C.; NMR (d.sub.6 DMSO) .delta.8.13(2H,d), 7.23(2H,d), 7.14(2H,d),
6.79(2H,d), 3.58(3H,s), 3.47(2H,s), 3.30(4H,t+H.sub.2 O), 2.57(2H,t),
2.46(4H,t), 2.32(2H,t), 1.56(4H,m); m/e 368 (M+H).sup.+ ; calculated for
C.sub.22 H.sub.29 N.sub.3 O.sub.2 0.5H.sub.2 O: C, 70.1; H, 8.0; N, 11.2.
found: C, 70.3; H, 8.2; N, 11.0%.
EXAMPLE 180
4-4-4-(4-Pyridyl)piperazin-1yl!methylphenyl!butyric acid, dihydrochloride
Following the method of Example 123 but starting from the product of
Example 178 and heating at 100.degree. C. for 4 hours instead of 1.5 hours
the title compound was prepared in 88% yield: m.p. 236.degree.-238.degree.
C.; NMR (D.sub.2 O) .delta.8.40(2H,d), 7.66(2H,d), 7.61(2H,d), 4.61(2H,s),
4.19(4H,b), 3.69(4H,b), 2.94(2H,t), 2.61(2H,t), 2.15(2H,m); m/e 340
(M+H).sup.+ ; calculated for C.sub.20 H.sub.25 N.sub.3
O.sub.2.2HCl0.5H.sub.2 O: C, 57.0; H, 6.6; N, 10.0. found: C, 57.2; H,
6.9; N,9.8%.
EXAMPLE 181
Mixture of 5-4-4-(4-pyridyl)piperazin-1-yl!methylphenyl!pentanoic acid
and 5-2-4-(4-pyridyl)piperazin-1-yl!methylphenyl!pentanoic acid,
dihydrochloride (4:1)
Following the method of Example 180, but starting from the crude mixture of
esters in Example 179, there was obtained the titled mixture of compounds
in 59% yield, as a white solid: NMR (D.sub.2 O) .delta.8.38(2H,d),
7.62(4H,m), 7.35(2H,d), 4.70(0.4H,s), 4.61(1.6H,s), 4.18(4H,b),
3.68(4H,b), 2.98(0.4H,t) 2.91(1.6H,t), 2.59(2H,t), 1.82(4H,m); m/e 354
(M+H).sup.+ ; calculated for C.sub.21 H.sub.27 N.sub.3
O.sub.2.2HCl0.5H.sub.2 O: C, 57.9; H, 6.9; N, 9.7. found: C, 59.6; H, 7.2;
N, 9.4%.
EXAMPLE 182
N-4-1-(4-Pyridyl)piperidin-4-yl!carboxamidophenyl!ethyl!-methanesulphami
de
Following the method of Example 170 but starting from methanesulphonyl
chloride instead of 1-butanesulphonyl chloride there was obtained after
evaporation of the reaction solvent an oily solid. This residue was
partitoned between ethyl acetate and a dilute hydrochloric acid solution.
Separation and then neutralisation of the aqueous phase with sodium
hydroxide solution gave a solid. This was collected by filtration, washed
with water and, on drying, gave the title compound in 93% yield: m.p.
238.degree.-240.degree. C.; NMR (d.sub.6 DMSO) .delta.9.91(1H,s),
8.13(2H,d), 7.08(2H,d), 7.47(1H,bt), 7.25(2H,d), 6.82(2H,d), 4.08(2H,d),
3.98(2H,bd), 2.89(2H,bt), 2.82(3H,s), 2.59(1H,m), 187 (2H, bd), 1.65 (2H,
dq); m/e 389 (M+H).sup.+ ; calculated for C.sub.19 H.sub.24 N.sub.4
O.sub.3 S.0.25H.sub.2 O: C, 58.1; H, 6.3; N, 14.3. found C, 58.2; H, 6.5;
N, 14.3%.
EXAMPLE 183
N-2-4-1-(4-Pyridyl)piperidin-4-yl!carboxamidophenyl!ethyl!methanesulphon
amide
Following the method of Example 182, but starting from
4-1-(4-pyridyl)piperidin -4-ylcarboxamido!phenethylamine, the title
compound was prepared in 90% yield: m.p. 193.degree.-195.degree. C.; NMR
(d.sub.6 DMSO) .delta.9.85(1H,s), 8.16(2H,d), 7.51(2H,d), 7.15(2H,d),
7.03(1H,t), 6.82(2H,d), 4.00(2H,bd), 3.13(2H,q), 2.90(2H,dt), 2.83(3H,s),
2.72(2H,t), 2.60(1H,m), 1.87(2H,dd), 1.65(2H,dq); m/e 403 (M+H).sup.+ ;
calculated for C.sub.20 H.sub.26 N.sub.4 O.sub.3 S.0.25H.sub.2 O: C, 59.0;
H, 6.6; N, 13.8. found, C, 59.0; H, 6.7; N, 13.7%.
The starting material was prepared as follows:
i) Following the method of Example 170i), but starting from
4-nitrophenethylamine, there was obtained
N-tertiary-butyloxycarbonyl-4-nitrophenethylamine in 82% yield: m.p.
94.degree.-95.degree. C.; NMR (d.sub.6 DMSO) .delta.8.14(2H,d),
7.46(2H,d), 6.89(1H,bt), 3.20(2H,q), 2.82(2H,t), 1.33(9H,s); m/e 267
(M+H).sup.+ ; calculated for C.sub.13 H.sub.18 N.sub.2 O.sub.4 : C, 58.6;
H, 6.81; N, 10.5. found: C, 58.3; H, 6.9; N, 10.5%.
ii) Following the method of Example 170ii) but starting from the product of
step i) above, there was obtained 4-(N-tertiary-butyloxycarbonyl
2-aminoethyl)aniline in 78% yield: m.p. 74.degree.-75.degree. C.; NMR
(d.sub.6 DMSO) .delta.6.81(2H,d), 6.73(1H,m), 6.47(2H,d), 4.82(2H,s),
3.02(2H,m), 2.50(2H,m+DMSO), 1.37(9H,s); m/e 237 (M+H).sup.+ ; calculated
for C.sub.13 H.sub.20 N.sub.2 O.sub.2 : C, 66.1; H, 8.5; N, 11.9; found C,
65.9; H, 8.9; N, 11.8%.
iii) Following the method of Example 170ii), but starting from the product
of step ii) above, was obtained after recrystallisation from methanol,
N-tertiary-butyloxycarbonyl
4-1-(4-pyridyl)piperidin-4-ylcarboxamido!phenethylamine in 62% yield:
m.p. 242.degree.-244.degree. C.; NMR (d.sub.6 DMSO) .delta.9.82(1H,s),
8.15(2H,d), 7.50(2H,d), 7.09(2H,d), 6.82(2H,d), 6.78(1H,m), 3.99(2H,bd),
3.10(2H,q), 2.90(2H,dt), 2.63(2H,t), 2.56(1H,m), 1.86(2H,dd), 1.65(2H,dq),
1.48(9H,m); m/e 425 (M+H).sup.+ ; calculated for C.sub.24 H.sub.32 N.sub.4
O.sub.3.0.5H.sub.2 O: C, 66.5; H, 7.7; N, 12.9. found: C, 66.5; H, 7.7; N,
12.9%.
iv) Following the method of Example 170iv) but starting from the product of
step iii) above there was obtained the dihydrochloride salt, m.p.
286.degree.-289.degree. C. To a stirred solution of the salt in water was
added 3 equivalents of 1 molar sodium hydroxide. After 1 hour the
precipitated solid was collected by centrifugation, washed with water and
on drying, gave 4-1-(4-pyridyl)piperidin-4-ylcarboxamido!phenethylamine
in 92% yield: m.p. 207.degree.-211.degree. C.; NMR (d.sub.6 DMSO+d.sub.4
acetic acid) .delta.8.18(2H,d), 7.58(2H,d), 7.18(4H,m) 4.22(2H,d),
3.28(2H,t), 3.05(2H,m), 2.83(3H,m), 2.00(2H,dd), 1.76(2H,dq); m/e 325
(M+H).sup.+ ; calculated for C.sub.19 H.sub.24 N.sub.4 O.0.5H.sub.2 O: C,
68.4; H. 7.6; N, 16.8. found: C, 68.2; H, 7.6; N, 16.7%.
EXAMPLE 184
N-2-4-1-(4-Pyridyl)piperidin-4-yl!carboxamidophenyl!ethyl!-4-methylpheny
lsulphonamide
Following the method of Example 183, but starting from
4-methylphenylsulphonyl chloride instead of methanesulphonyl chloride, the
title compound was obtained 81% yield: m.p. 175.degree.-178.degree. C.;
NMR (d.sub.6 DMSO) .delta.9.81(1H,s), 8.15(2H,d), 7.64(2H,d), 7.55(1H,t),
7.46(2H,d), 7.36(2H,d), 7.03(2H,d), 6.82(2H,d), 3.98(2H,bd), 3.90(4H,m),
2.60(3H,m), 2.37(3H,s), 1.85(2H,dd), 1.65(2H,dq), m/e 479 (M+H).sup.+ ;
calculated for C.sub.26 H.sub.30 N.sub.4 O.sub.3 S.H.sub.2 O: C, 62.9; H,
6.5; N, 11.3. found: C, 63.1; H, 6.3; N, 11.1%.
EXAMPLE 185
N-4-2-4-(4-Pyridyl)piperazin-1-yl!ethyl!phenyl!methyl-1-butanesulphonami
de
Triethylamine (0.41 ml) was added to a stirred suspension of
4-2-4-(4-pyridyl)piperazin-1-yl!ethyl!benzylamine, trihydrochloride (300
mg) in dry dichloromethane (20 ml). After 5 minutes, 1-butanesulphonyl
chloride (0.10 ml) was added and the mixture stirred overnight.
Dichloromethane (80 ml) was added and the solution washed with water
(2.times.25 ml), dried (MgSO.sub.4) and the solvent removed in vacuo,
Trituration of the residue with a small volume of ethyl acetate gave the
title compound, 50 mg, as an off-white solid: m.p. 154.degree.-156.degree.
C.; NMR (d.sub.6 DMSO) .delta.8.16(2H,d), 7.53(1H,t), 7.22(4H,m),
6.37(2H,d), 4.10(2H,d), 3.35(6H,m+H.sub.2 O), 2.81(4H,m), 2.54(4H,m+DMSO),
1.56(2H,m), 1.29(2H,m). 0.82(3H,t), m/e 417 (M+H).sup.+ ; calculated for
C.sub.22 H.sub.32 N.sub.4 O.sub.2 S.0.75H.sub.2 O: C, 61.5; H, 7.8;, 13.0.
found: C, 61.5; H, 7.6; N, 12.7%.
The starting material was prepare as follows:
i) A suspension of di-tert-butyl iminodicarboxylate (4.25 g) and finely
powdered anhydrous potassium hydroxide (1.1 g) in dry THF (60 ml) was
stirred for 2 hours. 2-(4-Bromomethylphenyl)ethanol (4.2 g) dissolved in
THF (40 ml) was added and the mixture stirred for 16 hours when further
anion prepared from di-tert-butyl iminodicarboxylate (4.25 g) and finely
powdered anhydrous potassium hydroxide (1.1 g) in dry THF (40 ml) was
added and stirring continued for 3 days. Ether (300 ml) was added and the
mixture washed with water and saturated sodium chloride solution, then
dried (MgSO.sub.4) and evaporated to give a colourless oil. Purification
by flash chromatography on silica, eluting with 1% v/v
methanol/dichloromethane gave N-di-tert-butyloxycarbonyl
4-1-(2-hydroxyethyl)!benzylamine, 6.1 g, as a clear oil: NMR (CDCl.sub.3)
.delta.7.25(2H,d), 7.17(2H,d), 4.75(2H,s), 4.37(1H,b), 3.35(2H,bt),
2.85(2H,t), 1.46(18H,s); m/e 352 (M+H).sup.+.
ii) A stirred, cooled (4.degree. C.), solution of the product from step i)
above (6.1 g) in dry dichloromethane (100 ml) was treated under argon with
triethylamine (3.1 ml), then methanesulphonyl chloride (1.6 ml) was added
dropwise over 15 minutes and stirring continued for 1 hour at 4.degree. C.
and 2 hours at ambient temperature. The dichloromethane was removed by
evaporation and the residue dissolved in ethyl acetate (250 ml). This
solution was washed with water and saturated sodium chloride solution,
then dried (MgSO.sub.4). Evaporation of the solvent gave
N-di-tert-butyloxycarbonyl-4-1-(2-methanensulphonyl-oxyethyl)!benzylamine
, 6.53 g, as an off-white solid: m.p. 66.degree.-68.degree. C.; NMR
(CDCl.sub.3) .delta.7.26(2H,d), 7.17(2H,d), 4.75(2H,s), 4.40(2H,t),
3.03(2H,t), 2.84(3H,s), 1.46(18H,s); m/e 452 (M+Na).sup.+.
iii) A mixture of the product from step ii) above (6.5 g) and
1-(4-pyridyl)piperazine (4.95 g) in acetonitrile (100 ml) was heated and
stirred at reflux temperature for 16 hours. The solvent was removed in
vacuo, the residue dissolved in dichloromethane (300 ml) and this solution
washed with water, then dried (MgSO.sub.4) and evaporated. The residue,
after purification by flash chromatography on silica, eluting with 10% v/v
methanol/dichloromethane gave N-di-tert-butyloxycarbonyl
4-2-4-(4-pyridyl)piperazin- 1-yl!ethyl!benzylamine, 2.25 g, as a
coloured gum: NMR (d.sub.6 DMSO) .delta.8.14(2H,d), 7.21(2H,d),
7.12(2H,d), 6.81(2H,d), 4.63(2H,s), 3.30(6H,m+H.sub.2 O), 2.75(2H,t),
2.53(4H,t+DMSO), 1.40(18H,s); m/e 497 (M+H).sup.+.
A solution of the product from step iii) above (2.0 g) dissolved in
methanol (40 ml) was treated with a 5 molar solution of dry hydrogen
chloride gas in methanol (8.0 ml) and the mixture stirred for 16 hours.
The solvent was removed in vacuo and the residue, on trituration with
ether, gave 4-2-4-(4-pyridyl)piperazin-1-yl!ethyl!benzylamine,
trihydrochloride, 1.86 g, as a pale yellow solid: m.p.
297.degree.-299.degree. C. dec; NMR (d.sub.6 DMSO) .delta.13.92(2H,b),
12.01(1H,b), 8.49(4H,m), 7.47(2H,m), 7.31(4H,m), 4.46(2H,b), 4.00(2H,q),
3.70(4H,b), 3.30(6H,m+H.sub.2 O; m/e 297 (M+H).sup.+ ; calculated for
C.sub.18 H.sub.24 N.sub.4.3HCl.3.5H.sub.2 O: C, 46.1; H, 7.3; N, 11.9.
found: C, 45.8; H, 7.1; N, 11.8%.
EXAMPLE 186
N-!4-2-4-(4-Pyridyl)piperazin-1-yl!ethyl!phenyl!methyl-4-methylphenylsulp
honamide
Following the method of Example 185, but starting from
4-methylphenylsulphonyl chloride instead of 1-butanesulphonyl chloride the
title compound was obtain in 69% yield, as a white solid: m.p.
180.degree.-182.degree. C.; NMR (d.sub.6 DMSO+d.sub.4 acetic acid)
.delta.8.21(2H,d), 7.70(2H,d), 7.47(2H,d), 7.19(6H,m), 3.96(2H,s),
3.80(4H,bt), 2.94(4H,bt), 2.86(4H,bs), 2.40(3H,s), m/e 451 (M+H).sup.+ ;
calculated for C.sub.25 H.sub.30 N.sub.4 O.sub.2 S.H.sub.2 O: C, 64.1; H,
6.8; N, 11.9. found: C, 63.9; H, 6.6; N, 11.6%.
EXAMPLE 187
Ethyl 6-4-(4-pyridylamino)phenoxy!hexanoate
Trifluoroacetic acid (3 ml) was added to a stirred solution of ethyl
6-4-N-(4-pyridyl)-N-tertiary-butyloxycarbonylamino!phenoxy!- hexanoate
(260 mg) dissolved in dichloromethane (3 ml). After 18 hours the solvents
were removed in vacuo and the residual gum dissolved in dichloromethane.
This solution was treated with a saturated solution of sodium hydrogen
carbonate. The organic phase was washed with water, dried and evaporated.
Trituration of the residue with hexane gave the title compound, 120 mg, as
a white solid: m.p. 104.degree.-106.degree. C.; NMR (CDCl.sub.3)
.delta.8.22(2H,d), 7.12(2H,d), 6.90(2H,d), 6.64(2H,dd), 5.82(1H,s),
4.13(2H,q), 3.97(2H,t), 2.34(2H,t), 1.80(2H,m), 1.70(2H,m), 1.53(2H,m),
1.27(3H,t); m/e 329 (M+H).sup.+ ; calculated for C.sub.19 H.sub.24 N.sub.2
O.sub.3.0.25H.sub.2 O:C, 68.6; H, 7.4; N, 8.4. found: C, 68.8; H, 7.3; N,
8.2%.
The starting material was prepared as follows:
i) A stirred mixture of 4-chloropyridine hydrochloride (2 g) and
4-methoxyaniline (4.9 g) was heated at 140.degree. C. for 5 hours. After
cooling the residue was dissolved in dichloromethane (250 ml), the
solution extracted with water (2.times.100 ml). The aqueous extracts were
treated with sodium hydroxide solution and then extracted with ethyl
acetate (4.times.100 ml). The combined organic extracts were washed with
water, and saturated sodium chloride solution, then dried and the solvent
evaporated. Purification by flash chromatography on silica, eluting with
10% v/v methanol/dichloromethane gave 4-(4-pyridylamino)methoxybenzene, 2
g, as a fawn solid: m.p. 159.degree.-160.degree. C.; NMR (d.sub.6 DMSO)
.delta.8.47(1H,s) 8.09(2H,d), 7.10(2H,d), 6.92(2H,d), 6.70(2H,dd),
3.73(3H,s); m/e 201 (M+H).sup.+ ; calculated for C.sub.12 H.sub.12 N.sub.2
O.sub.3 : C, 72.0; H, 6.0; N, 14.0. found: C, 71.4; H, 6.1; N, 13.8%.
ii) A mixture of the product from step i) above (2.0 g) and 48% w/v
hydrobromic acid (30 ml) was heated at 140.degree. C. for 4 hours. The
cooled solution was neutralised with 0.880 ammonia solution and then
extracted four times with ethyl acetate. The combined organic extracts ere
washed with water and saturated sodium chloride solution, then dried
(MgSO.sub.4) and evaporated. Purification by flash chromatography on
silica, eluting with 10 to 20% v/v methanol/dichloromethane gave
4-(4-pyridylamino)phenol, 0.78 g as an off-white solid: m.p.
246.degree.-248.degree. C.; NMR (CDCl.sub.3 +d.sub.6 DMSO)
.delta.8.92(1H,b), 8.09(2H,d), 7.31(1H,s), 7.00(2H,d), 6.79(2H,d),
6.67(2H,dd); m/e 187 (M+H).sup.+.
iii) A mixture of the product from step ii) above (0.78 g),
di-tertiary-butyl dicarbonate (0.91 g), triethylamine (0.59 ml),
1,2-dimethoxymethane (20 ml) and water (10 ml) was stirred for 18 hours.
The solvents were removed in vacuo and the residue partitioned between
ethyl acetate and water. The aqueous phase was extracted two times with
further ethyl acetate and the combined organic extracts washed with water
and brine, dried (MgSO.sub.4) and evaporated to a small volume when
crystallisation occurred. Collection by filtration gave
4-N-(4-pyridyl)-N-tertiary-butyloxycarbonylamino!phenol, 1.07 g as a
white crystalline solid: m.p. 192.degree.-194.degree. C. (dec); NMR
(CDCl.sub.3) .delta.8.28(2H,dd), 7.18(4H,s), 6.76(2H,dd), 6.03(1H,bs),
1.57(9H,s); m/e 287 (M+H).sup.+.
iv) Sodium hydride (50% w/w dispersion in mineral oil, 55 mg) was added
under argon to a stirred solution of the product from step iii) above (300
mg)in dry DMF (5 ml). After five minutes, ethyl 6-bromohexanoate (0.20 ml)
was added and the mixture stirred for 16 hours. The DMF was evaporated in
vacuo and the residue partitioned between dichloromethane and water. The
aqueous phase was extracted with further dichloromethane. The combined
organic extracts were washed with water then dried, and evaporated. The
residue was purified by chromatography on alumina, eluting with
dichloromethane and the 1% v/v methanol/dichloromethane. Evaporation of
the appropriate fractions gave ethyl
6-4-N-(4-pyridyl)-N-tertiary-butyloxycarbonylamino!phenoxy!hexanoate,
260 mg, as a yellow gum: NMR (CDCl.sub.3) .delta.8.40(2H,dd), 7.16(2H,dd),
7.07(2H,m), 6.90(2H,m), 4.13(2H,q), 3.98(2H,t), 2.34(2H,t), 1.78(4H,m),
1.57(2H,m), 1.44(9H,s), 1.26(3H;t); m/e 429 (M+H).sup.+.
EXAMPLE 188
6-4-(4-Pridylamino)phenoxy!hexanoic acid hydrochloride
Following the method of Example 123, but starting from the product of
Example 187 and heating at 100.degree. C. for 16 hours instead of 1.5
hours, the title compound was obtained in 80% yield as a freeze-dried
solid: NMR (d.sub.6 DMSO) .delta.13.63(1H,b), 11.95(1H,b), 10.49(1H,s),
8.21(2H,d), 7.26(2H,d), 6.98(4H,m), 4.00(2H,t), 2.23(2H,t), 1.70(2H,m),
1.55(2H,m), 1.45(2H,m); m/e 301 (M+H).sup.+ ; calculated for C.sub.17
H.sub.20 N.sub.2 O.sub.2.HCl. 1.25H.sub.2 O: C, 56.8; H 6.6; N, 7.8.
found: C, 56.8; H, 6.6; N, 7.4%.
EXAMPLE 189
N-4-(4,4Pyridyl)piperazin-1-yl!benzoyl!-N-methylglycine, trifluoroacetate
To a solution of ethyl
N-4-(4-pyridyl)piperazin-1-yl!benzoyl!-N-methylglycinate (78 mg) in
methanol (2 ml) as added sodium hydroxide solution (1N, 0.4 ml) and the
resultant mixture was stored at room temperature for 1 hour. The pH of the
reaction mixture was adjusted to 2 by addition of 2N HCl (aq) (0.45-0.5
ml) and the resultant solution was purified by preparative rp-hplc on a
DYNAMAX C-18, 60A 83-201-C! column using an acetonitrile/water mobile
phase containing 0.1% trifluoroacetic acid, to give, after lyophilisation,
the title compound (46 mg) as a glass: NMR (d.sub.6 DMSO)
.delta.2.98(3H,s), 3.45(4H,m), 3.86(4H,m), 4.07(2H,s), 6.97(2H,d),
7.23(2H,d), 7.31(2H,m), 8.27(2H,d); mZ 355 (M+H).sup.+ ; calculated for
C.sub.19 H.sub.22 N.sub.4 O.sub.3. 1.0 CF.sub.3 CO.sub.2 H. 1.25 H.sub.2
O: C, 51.4%; H, 5.24%; N, 11.4%; found: C. 51.2%; H, 4.9%; N, 11.2%.
The starting material was prepared as follows:
To a stirred mixture of 4-(4-pyridyl)piperazin-1-yl!benzoic acid (prepared
as in Example 56(i) (311 mg), HOBt.H.sub.2 O (170 mg) and HBTU (416 mg) in
DMF (5 ml) at 0.degree.-5.degree. C. under argon was added
diisopropylethylamine (0.75 ml). The ice-bath was removed and the reaction
mixture was stirred at room temperature for 15 minutes before solid
sarcosine, ethyl ester hydrochloride (154 mg) was added. The reaction
mixture was stirred at room temperature under argon overnight then diluted
with dichloromethane (30 ml) and water (30 ml). The organic layer was
separated and the aqueous layer was re-extracted with dichloromethane (30
ml). The combined organic extracts were washed with water, saturated
sodium bicarbonate solution, water, dried (MgSO.sub.4) and evaporated. The
residue was purified by filtration through a short bed of activated (grade
II) alumina by elution with ethyl acetate/methanol, 5:1, to give ethyl
N-(4-(4-pyridyl)piperazin-1-ylbenzoyl)-N-methylglycinate (92 mg) as an
amorphous solid: NMR (d.sub.6 DMSO+CD.sub.3 CO.sub.2 D) .delta.1.18(3H,t),
2.98(3H,s), 3.44(4H,m), 3.79(4H,m), 4.11(4H,m), 6.94(2H,d), 7.12(2H,d),
7.31(2H,brd), 8.19(2H,d); m/Z 383 (M+H).sup.+.
EXAMPLE 190
N4-(4-Pyridyl)piperazin-1-yl!benzoyl!-L-phenylalanine, methyl ester
In a similar manner to Example 189i), 4-(4-pyridyl)piperazin-1-yl!benzoic
acid (311 mg), p-toluene sulphonic acid, monohydrate (418 mg),
HOBt.H.sub.2 O (170 mg), HBTU (416 mg), DMF (5 ml), diisopropylethylamine
(1.13 ml) and L-phenylalanine, methyl ester hydrochloride (216 mg) gave,
after filtration through a bed of neutral alumina and elution with ethyl
acetate/methanol, 6:1, the titled compound as a white crystalline solid
(336 mg); m.p. 139.degree.-143.5.degree. C.; NMR (CDCl.sub.3)
.delta.32.6(2H,m), 3.50(8H,m), 3.76(3H,s), 5.09(1H,m), 6.46(1H,d),
6.70(2H,m), 6.90(2H,d), 7.13(2H,m), 7.28(3H,m), 7.68(2H,d), 8.31(2H,m);
m/z 445 (M+H).sup.+ ; calculated for C.sub.26 H.sub.28 N.sub.4 O.sub.3.
1.0 H.sub.2 O: C, 67.5%, H, 6.54%; N, 12.1%; found: C, 67.6%; H, 6.4%;
12.1%.
EXAMPLE 191
N-4(4-Pyridyl)piperazin-1-yl!L-phenylalanine
To a solutionof the product of Example 190 (100 mg) in methanol (2.2 ml)
was added sodium hydroxide solutiin (1N, 0.44 ml). The resultant mixture
was stored at room temperature with occasional swirling of 2.5 hr, then
the pH was adjusted to 5 by addition of 2N HCl (aq) (0.22 ml) and 50%
aqueous acetic acid (3 drops). The mixture was filtered and evaporated to
dryness. The residue was crystallized from hot water containing a trace of
methanol to give the title compound as a pale yellow crystalline solid (47
mg); NMR (d.sub.6 DMSO+CD.sub.3 CO.sub.2 D) .delta.3.05(1H,m), 3.15(1H,m),
3.45(4H,m), 3.77(4H,m), 4.58(1H,m), 6.90(2H,d), 7.12(2H,d), 7.22(5H,m),
7.70(2H,d), 8.19(2H,d); m/Z 431 (M+H).sup.+ ; calculated for C.sub.25
H.sub.26 N.sub.4 O.sub.3. 0.75 H.sub.2 O: C, 67.6%; H, 6.24%; N, 12.6%;
found: C, 67.6%; H, 6.0%; N, 12.5%.
EXAMPLE 192
(S)-3-N-2-Phenenthyl!carboxamido!-3-4-4-(4-pyridyl)piperazin-1-yl!!-ben
zamidopropionic acid
To a stirred suspension to benzyl
(S)-3-N-2-phenethyl!carboxamido!-3-4-4-(4-pyridyl)piperazin-1-yl!!!ben
zamidopropionate (120 mg) in methanol (3 ml) was added sodium hydroxide
solution (1N, 0.5 ml). Within 15 minutes all the solid had dissolved, and
the reaction mixture was stirred at room temperature for a further 2 hr.
The pH was then adjusted to 5 by addition of 2N HCl (aq) (0.25 ml) and 50%
aqueous acetic acid (3 drops). The mixture was filtered and evaporated to
dryness. The residue was crystallised from hot water containing a trace of
methanol to give the title compound as a pale yellow crystalline solid (66
mg); NMR (d.sub.6 DMSO+CD.sub.3 CO.sub.2 D) .delta.2.70(4H,m), 3.30(2H,t),
3.56(4H,m), 3.85(4H,m), 4.73(1H,m), 6.99(2H,d), 7.20(7H,m), 7.80(2H,d),
8.25(2H,d); m/Z 502 (M+H).sup.+ ; calculated for C.sub.28 H.sub.31 N.sub.5
O.sub.4. 1.25 H.sub.2): C, 64.2%; H, 6.44%; N, 13.4%; found: C, 64.2%; H,
6.4%; N, 13.6%.
The starting material was prepared as follows:
i) Boc-L-aspartic acid, 2-phenethylamide, .beta.-benzyl ester (preparation
described in Samanen, J. et al (1991), J. Med. Chem., 34, 3114-25) (2 g)
was dissolved in a mixture containing dichloromethane (10 ml) and
trifluoroacetic acid (10 ml). The resultant pale yellow solution was
stored at room temperature for 2 hr after which time the mixture was
evaporated to dryness. The oily product was dissolved in dry ether and
re-evaporated. This procedure was repeated twice more to give a viscous
oily residue containing the trifluoracetic salt of L-aspartic acid,
2-phenethylamide, .beta.-benzyl ester (2.07 g) which was used without
further purification.
ii) In a similar manner to Example 189i);
4-(4-pyridyl)piperazin-1-yl!benzoic acid (311 mg), p-toluene sulphinc
acid, monohydrate (627 mg), HOBt.H.sub.2 O (170 mg), HBTU (416 mg), DMF
(15 ml), diisopropylethylamine (1.5 ml) and L-aspartic acid,
2-phenethylamide, .beta.-benzyl ester (440 mg) gave, after purification by
flash chromatography on silica, eluting solvent, ethyl acetate/methanol,
4:1 to 2:1, benzyl
(S)-3-(N-2-phenethyl!-carboxamido)-3-44-(4-pyridyl)piperazin-1-yl!!!ben
zamidopropionate (268 mg) as a white crytalline solid: NMR (d.sub.6 DMSO)
.delta.2.70(2H,t), 2.76(1H,m), 2.88(1H,m), 3.25(2H,m), 3.44(4H,m),
3.50(4H,m), 5.08(2H,s), 6.89(2H,d), 7.02(2H,d), 7.20(5H,m), 7.31(5H,m),
7.78(2H,d), 7.90(1H,t), 8.20(2H,d), 8.36(1H,d); m/Z 592 (M+H).sup.+ ;
calculated for C.sub.35 H.sub.37 N.sub.5 O.sub.4.0.25 H.sub.2 O: C, 70.5%;
H, 6.34%; N, 11.7%; found: C, 70.5%; H, 6.3%; N, 11.7%.
EXAMPLE 193
(R)-3-N-2-Phenethyl!carboxamido!-3-4-4-(4-pyridyl)piperazin-1-yl!!!-ben
zamidopropionic acid
Following the method of Example 192, but starting from benzyl
(R)-3-N-2-phenethyl!carobxamido!-3-4-4-(4-pyridyl)piperazin-1-yl!!!ben
zamidopropionate instead of the corresponding (S)-isomer, the titled
compound was obtained as a pale yellow crystalline solid in 33% yield: NMR
(d.sub.6 DMSO+CD.sub.3 CO.sub.2 D) .delta.2.71(4H,m), 3.29(2H,t),
3.53(4H,m), 3.83(4H,m), 4.72(1H,m), 6.99(2H,d), 7.17(7H,m), 7.77(2H,d),
8.24(2H,d); m/Z 502 (M+H).sup.+ ; calculated for C.sub.28 H.sub.31 N.sub.5
O.sub.4. 1.25 H.sub.2 O: C, 64.2%; H, 6.44%; N, 13.4%; found: C, 64.2%; H,
6.4%; N, 13.3%.
The starting material was prepared as follows:
i) Boc-D-aspartic acid, 2-phenethylamide, .beta.-benzyl ester (preparation
described in Rodriquez, M. et al (1989), J. Med. Chem., 32, 522-8) (1 g)
was dissolved in acetonitrile (5 ml) with gently warming, then cooled to
room temperature before excess ethereal HCl (5 ml) was added. The reaction
mixture was stored at room temperature overnight then evaporated to
dryness. The pale yellow oily residue was triturated with dry ether and
re-evaporated. This procedure was repeated twice more to give a
hygroscopic oil residue containing the hydrochloride salt of D-aspartic
acid, 2-phenethylamide, .beta.-benzyl ester (0.55 g) which was used
without further purification.
ii) In a similar manner to Example 56, the hydrochloride salt of D-aspartic
acid, 2-phenethylamide, .beta.-benzyl ester (363 mg),
4-(4-pyridyl)piperazin-1-yl!benzoyl chloride (377 mg),
diisopropylethylamine (0.87 ml) and DMF (5 ml) gave benzyl
(R)-3-N-2-phenethyl!carboxamido!-3-4-4-4-pyridyl)piperazin-1-yl!!!benz
amidopropionate (510 mg) as an off-white, amorphous solid: m/Z 592
(M+H).sup.+.
EXAMPLE 194
(S)-3-N-(2-Phenethyl)carboxamido!-3-N-N-2-4-(4-pyridyl)piperazin-1-yl!a
cetyl!glycyl!aminopropionic acid, trifluoroacetate
In a similar manner to Example 189, benzyl
(S)-3-N-(2-phenethyl)carbxoamido!-3-N-N-2-4-(4-pyridyl)piperazin-1-yl!
acetyl!glycyl!aminopropionate (240 mg), sodium hydroxide solution (1N, 1.4
ml) and methanol (4 ml) gave, after 6 hr, followed by acidification to pH
4, preparative rp-hplc and lyophilisation, the title compound (224 mg) as
a colourless glass: NMR (d.sub.6 DMSO+CD.sub.3 CO.sub.2 D)
.delta.2.58(2H,m), 2.74(2H,t), 3.17(4H,m), 3.31(2H,t), 3.70(2H,m),
3.91(6H,m), 4.62(1H,m), 7.21(7H,m), 8.25(2H;d); m/Z 497 (M+H).sup.+ ;
calculated for C.sub.25 H.sub.32 N.sub.6 O.sub.5. 2.0 CF.sub.3 CO.sub.2 H.
1.0 H.sub.2 O: C, 46.9%; H, 4.89%; N, 11.3%; found: C, 4.67%; H, 4.8%; N,
11.1%.
The starting material was prepared as follows:
i) In a similar manner to Example 192i), N-(N'-Boc-glycyl)-L-aspartic acid,
2-phenethylamide, .beta.-benzyl ester (preparation described in Samanen,
J. et al (1991), J. Med. Chem., 34, 3114-25) (370 mg), dichloromethane
(2ml) and trifluoroacetic acid (2 ml) gave a hygroscopic oil containing
the trifluoroacetate salt of N-glycyl-L-aspartic acid, 2-phenethylamide,
.beta.-benzyl ester (340 mg), which was used without further purification.
ii) In a similar manner to Example 189i),
1-(4-pyridyl)-4-carboxymethylpiperazine dihydrochloride (220 mg), HBTU
(284 mg), HOBt.H.sub.2 O (115 mg), DMF (3 ml), diisopropylethylamine (0.53
ml) and the trifluoroacetate salt of N-glycyl-L-aspartic acid,
2-phenethylamide, .beta.-benzyl ester (340 mg) gave, after purification by
flash chromatography on silica, eluting solvent, dichloromethane/methanol,
9:1 to 4:1, benzyl
(S)-3-(N-2-phenethyl!carboxamido)-3-N-N-2-4-(4-pyridyl)piperazine-1-yl
!acetyl!glycyl!-aminopropionate (249 mg) as a colourless foam: NMR (d.sub.6
DMSO+CD.sub.3 CO.sub.2 D).delta. 2.63(4H,m), 2.69(2H,t), 2.72(2H,m),
3.06(2H,s), 3.25(2H,m), 3.64(4H,m), 3.78(2H,q), 4.62 (1H,m), 5.05(2H,s),
7.06(2H,d), 7.10-7.35(10H,m), 8.15(2H,d); m/Z 587 (M+H.sup.+.
EXAMPLE 195
3-4-4-(4-Pyridyl)piperazin-1-yl!butyryl!aminopropionic acid,
trifluoroacetate
In a similar manner to Example 189, methyl
3-4-4-(4-piperazin-1-yl!-butyryl!aminopropionate (163 mg), and sodium
hydroxide solution (1N, 1.5 ml) gave, after preparative rp-hplc and
lyophilisation, a glassy solid which was crystallised from hot
acetonitrile/ether to give the title compound, trifluoroacetate salt (165
mg) as a colourless cystalline solid: m.p. 129.degree.-131.degree. C.; NMR
(d.sub.6 DMSO+CD.sub.3 CO.sub.2 D) .delta. 1.89(2H,m), 2.19(2H,t),
2.37(2H,t, 3.08(2H,m), 3.25(2H,t), 3.32(4H,m), 3.91(4H,m), 7.26(2H,d),
8.32(2H,d); m/Z 321 (M+H).sup.+ ; calculated for C.sub.16 H.sub.24 N.sub.4
O.sub.3. 1.9 CF.sub.3 CO.sub.2 H: C, 44.3%; H, 4.86%; N, 10.4%; found: C,
44.5%; H, 4.9%; N, 10.3%.
The starting material was prepared as follows:
i) To a stirred suspension of 1-(4-pyridyl)piperazine (5 g) in dry DMF (30
ml) under argon at 0.degree.-5.degree. C. was added, in portions, a solid
dispersion of sodium hydride (60%) in mineral oil (1.23 g). On completion
of the addition, the ice-bath was removed and the reaction was stirred
vigorously at room temperature. After 45 min, a solution of ethyl
4-bromobutyrate (5.85 g) in dry DMF (5 ml) was added and the reaction
mixture was stirred at room temperature for 2 hr then diluted carefully
with water (50 ml) and poured into dichloromethane (50 ml). The organic
layer was separated and the aqueous layer was re-extracted with
dichloromethane (50 ml). The combined organic extracts were washed with
water, then extracted with 1N HCl(aq) (40 ml). The acidic extract was
washed with dichloromethane (40 ml) and the aqueous layer was basified by
addition of sodium hydroxide solution (1N, 40 ml) and saturated sodium
bicarbonate solution (10 ml). This mixture was then extracted with
dichloromethane (50 ml) and the organic extract was washed with water,
dried (MgSo.sub.4) and evaporated. The resultant pale yellow oil was
dissolved in ether (50 ml) and to this solution was added excess ethereal
HCl. An amorphous solid precipitated immediately, which was triturated,
collected and washed with dry ether to give ethyl
4-(4-pyridyl)piperazin-1-yl!-butyrate, dihydrochloride salt (5.09 g) as a
white hydrosopic solid: NMR (d.sub.6 DMSO+CD.sub.3 CO.sub.2 D) .delta.
1.13(3H,t), 1.95(2H,m), 2.38(2H,t), 3.10(2H,m, 3.35(4H,brm), 3.97(4H,brm),
4.02(2H,q), 7.19(2H,d), 8.25(2H,d); m/Z 278 (M+H).sup.+.
A mixture of the product of step i) (5 g) and conc. HCl (50 ml) was heated
at 100.degree. C. for 45 min. The resultant solution was evaporated to
dryness and the residue dissolved again in conc. HCl and heated to
100.degree. C. for a further 45 min. The reaction mixture was evaporated
to dryness, and the residue was twice triturated with toluene, and
evaporated to dryness, collected and washed with ether. The crude product
was crystallised from hot methanol/ether to give
4-(4-pyridyl)piperazine-1-yl!butyric acid, dihydrochloride as an
off-white crystalline solid (3.45 g): m.p. 280.degree.-300.degree. C.
(dec); NMR (d.sub.6 DMSO) .delta. 2.00(2H,m), 2.36(2H,t), 3.12(2H,m),
3.00-3.70(4H,vbrm), 3.50-4.50(4H,vbrm), 7.30(2H,d), 8.35(2H,d),
12.2(1H,vbr); m/Z 250 (M+H).sup.+ ; calculated for C.sub.13 H.sub.19
N.sub.3 O.sub.2.2.0 HCl. 0.5 H.sub.2 O: C, 47.1%; H, 6.69%; N, 12.7%;
found: C, 47.5%; H, 6.7%; N, 12.5%
iii) In a similar manner to Example 189i), the product of step ii) (403
mg), HBTU (474 mg), HOBt.H.sub.2 O (190 mg), DMF (5 ml),
diisopropylethylamine (1.31 ml) and methyl 3-aminopropionate,
hydrochloride (175 mg) gave, after purification by flash chromatography on
silica, eluting solvent dichloromethane/methanol, 4:1 to 3:1, methyl
3-4-4-(4-pyridyl)-piperazine-1-yl!butyryl!aminopropionate (168 mg) as an
amorphous solid: NMR (d.sub.6 DMSO+CD.sub.3 CO.sub.2 D) .delta.
1.74(2H,m), 2.14(2H,t), 2.42(2H,t), 2.50(2H,t), 2.62(4H,m), 3.33(2H,t),
3.65(7H,m), 7.12(2H,d), 8.22(2H,d); m/Z 335 (M+H).sup.+.
EXAMPLE 196
5-(4-Pyridyl)piperazin-1-yl!pentanoic acid, dihydrochloride salt
Following the method of Example 195ii), but staring from ethyl
5-(4-pyridyl)piperazine-1-yl!pentanoate, dichydrochloride salt instead of
ethyl 4-(4-pyridyl)piperazin-1-yl!butyrate, dihydrochloride salt, the
title compound was isolated after recrystallisation from wet ethanol, as
an off-white crystalline solid in 59% overall yield: m.p.
294.degree.-297.degree. C. (dec); NMR (d.sub.6 DMSO+CD.sub.3 CO.sub.2 D)
.delta. 1.62(2H,m, 1.80(2H,m), 2.32(2H,t), 3.18(2H,m), 3.41(4H,m),
4.05(4H,m) 7.29(2H,d, 8.34(2H,d; m/Z 264 (M+H).sup.+ ; calculated for
C.sub.14 H.sub.21 N.sub.3 O.sub.2. 2.0 HCl: C, 50.0%; H, 6.89%; N, 12.5%;
found: C, 50.5% H, 7.2%; N, 12.2%.
The starting material was prepared as follows:
i) Following the method of Example 195i), but starting from ethyl
5-bromovalerate instead of ethyl 4-bromobutyrate, ethyl
5-(4-pyridyl-piperazin-1-yl!pentanoate, dihydrochloride salt was isolated
as a white hygroscopic solid 43% overall yield: NMR (d.sub.6 DMSO+CD.sub.3
CO.sub.2 D) .delta. 1.21(3H,t), 1.62(2H,m), 1.77(2H,m), 2.38(2H,t),
3.16(2H,m), 3.42(4H,m), 4.05(4H,m), 4.08(2H,q), 7.29(2H,d), 8.34(2H,d);
m/Z 292 (M+H).sup.+.
EXAMPLE 197
Methyl 3-5-4-(4-pyridyl)piperazine-1-yl!petanoyl!aminopropionate
In a similar manner to Example 189i), the product of Example 196 (840 mg),
HBTU (950 mg), HOBt.H.sub.2 O (380 mg), DMF (10 ml), diisopropylethylamine
(2.6 ml) and methyl 3-aminopropionate, hydrochloride (280 mg) gave, after
purification by flash chromatography on neutral alumina, eluting solvent
ethyl acetate/methanol, 50:1 to 4:1, the title compound (303 mg) as a
white crystalline solid: m.p. 118.degree.-122.degree. C.; NMR (d.sub.6
DMSO) .delta. 145(4H,m), 2.05(2H,t), 2.27(2H,t, 2.42(6H,m), 3.26(6H,m),
3.58(3H,s), 6.78(2H,m), 7.83(1H,brt), 8.12(2H,m); m/Z 349 (M+H).sup.+ ;
calculated for C.sub.18 H.sub.28 N.sub.4 O.sub.3 : C, 62.0%; H, 8.1%; N,
16.1%; found: C, 62.2%; H, 8.4%; N, 16.0%.
EXAMPLE 198
3-5-4-(4-Pyridyl)piperazine-1-yl!pentanoyl!aminopropionic acid
In a similar manner to Example 189, the product of Example 197 (160 mg),
methanol (5 ml) and sodium hdyroxide solution (1N, 1.4 ml) gave, after
preparative rp-hplc and lyophilisation, a glassy solid which was
crystallised from hot acetonitrile/ether to give the title compound,
trifluoroacetate salt (160 mg) as a colourless cystalline solid: m.p.
176.degree.-180.degree. C.; NMR (D.sub.6 DMSO+CD.sub.3 CO.sub.2 D) .delta.
1.64(4H,m), 2.18(2H,t), 2.45(2H,t), 3.12(2H,t),3.30(2H,t), 3.37(4H,m),
3.97(4H,m), 7.26(2H,d), 8.33(2H,d); m/Z 335 (M+H).sup.+ ; calculated for
C.sub.17 H.sub.26 N.sub.4 O.sub.3. 2.0 CF.sub.3 CO.sub.2 H: C, 44.8%; H,
5.02%; N, 9.96%; found: C, 44.6%; H, 5.0%; N, 9.8%.
EXAMPLE 199
4-Oxo-4-4-4-(4-pyridyl)piperazine-1-yl!phenyl!aminobutyric acid
To a solution of 1-(4-aminophenyl)-4-(4-pyridyl)piperazine (100 mg) in DMF
(8ml) was added succinic anhydride (79 mg). The reaction mixture was
stirred at room temperature for 2.5 hr and a precipitate was collected,
washed with DMF and ethanol, then dried to give the title compound (106
mg) as a beige-coloured solid: m.p. 263.degree.-264.degree. C.; NMR
(d.sub.6 DMSO+CF.sub.3 CO.sub.2 H) .delta. 2.68(4H,m), 3.80(4H,m,
4.19(4H,m), 7.20(2H,d), 7.56(2H,d), 7.82(2H,d), 8.21(2H,d), 9.62(1H,s);
m/Z 355 (M+H).sup.+ ; calculated for C.sub.19 H.sub.22 N.sub.4 O.sub.3.
0.4 H.sub.2 O: C, 63.1%; H, 6.36%; N, 15.5%; found: C, 63.1%; H, 6.4%; N,
15.7%.
The starting material was prepared as follows:
i) To an intimate mixture of 4-(4-pyridyl)piperazin-1-yl!benzoic acid
(Example 56i)) (500 mg) and hydroxylamine hydrochloride (13.5 mg) was
added polyphosphoric acid (16 g). The resultant mixture was heated to
160.degree. C. and maintained at that temperature with stirring for 30
min. The mixture was then allowed to cool to approximately 100.degree. C.
before crushed ice, followed by 15% potassium hydroxide solution to give a
pH 11 of were added. The suspension was allowed to cool to room
temperature and the precipitate was collected, washed with water and
air-dried to give 1-(4-aminophenyl)-4-(4-pyridyl)piperazine (159 mg) as a
light brown solid: m.p. 204.degree.-208.degree. C.; NMR (d.sub.6 DMSO)
.delta. 3.00(4H,m), 3.41(4H,m), 4.65(2H,brs), 6.51(2H,d), 6.73(2H,m),
6.85(2H,d), 8.18(2H,d); m/Z 255 M+H) .sup.+.
EXAMPLE 200
4-4-4-(4-Pyridyl)piperazine-1-yl!phenoxy!butyric acid, hydrochloride salt
A mixture of the product from Example 51 (1.5 g) and methanol (80 ml) was
heated to reflux with stirring, and solid pyridine hydrochloride (0.5 g)
was added. Heating was stopped and ethyl acetate (10 ml) was added. The
reaction mixture was evaporated until a slight turbidity was observed. On
further cooling, a precipitate formed which was collected, washed with
ethyl acetate and dried to give the title compound (1.33 g) as a beige
solid: m.p. >240.degree. C. (dec); NMR (d.sub.6 DMSO) .delta. 1.90(2H,m),
2.36(2H,t), 3.17(4H,m), 3.83(4H,m), 3.91(2H,t), 6.89(4H,q), 7.26(2H,d),
8.25(2H,d), 1.21(1H,br), 13.75(1H,br); m/Z 342 (M+H).sup.+ ; calculated
for C.sub.19 H.sub.23 N.sub.3 O.sub.3. 1.0 HCl: C, 60.4%; H, 6.4%; N,
11.1%; found: C, 60.0%; H, 6.4%, N, 10.8%.
EXAMPLE 201
N-2-Methoxyethyl-4-4-4-(4-pyridyl)piperazine-1-yl!phenoxy!butyramide,
trifluoroacetate
A solution of methoxyethylamine (0.9 ml) in dry dichloromethane (5 ml) was
added dropwise to a stirred solution of trimethylaluminium, 2M in toluene
(5 ml) at 5.degree.-10.degree. C. under argon. On completion of the
addition, the ice-bath was removed and the reaction mixture was stirred at
room temperature for 1 hr before a solution of the product of Example 50
(0.62 g) in dichloromethane (5 ml) was added dropwise. The reaction
mixture was heated to reflux under argon and stirred at reflux for 2 hr.
The reaction mixture was then cooled to room temperature and diluted with
dichloromethane (20 ml). A solution of methanol/dichloromethane, 1:1 (3
ml) was then added dropwise with stirring. The reaction mixture was
further diluted with dichloromethane (10 ml), methanol, (3 ml) and water
(5 ml). The organic layer was separated, dried (Na.sub.2 SO.sub.4) and
evaporated to dryness. The residue was purified by preparative rp-hplc on
a DYNAMAX C-18, 60A 83-201-C! column using an acetonitrile/water mobile
phase containing 0.1% trifluoroacetic acid, to give, after lyophilisation,
the title compound (56 mg) as an off-white solid: NMR (d.sub.6 DMSO)
.delta. 1.89(2H,m), 2.22(2H,t), 3.18(6H,m), 3.23(3H,s), 3.32(2H,t),
3.85(6H,m), 6.90(4H,q), 7.28(2H,d), 7.88(1H,brt), 8.25(2H,d); m/Z 399
(M+H).sup.+ ; calculated for C.sub.22 H.sub.30 N.sub.4 O.sub.3. 1.7
CF.sub.3 CO.sub.2 H: C; 51.5%; H, 5.4%; N, 9.5%; found: C, 51.4%; H, 5.6%;
N, 9.3%.
EXAMPLE 202
4-2-4-(4-Pyridyl)piperazine-2-one-1-yl!acetyl!phenoxyacetic acid
monohydrochloride
A solution of methyl 4-2-(piperazin-2-one-1-yl)acetyl!phenoxyacetate
(0.347 g), 4-chloropyridine hydrochloride (0.19 g) and triethylamine
(0.178 g) in water (8 ml) and dioxan (1 ml) was heated on a steam bath for
2 hours and then evaporated to dryness. The residue was triturated with
water (2 ml) and filtered. The solid thus obtained was recrystallised from
water to give the title compound (0.187 g), m.p. 275.degree.-277.degree.
C.; NMR (d.sub.6 DMSO) .delta. 8.33(2H, d), 8.0(2H,d), 7.21(2H,d),
7.1(2H,d), 4.97(2H,s), 3.94(2H,m), 3.59(2H,m); m/e 370(M+H.sup.+ ;
calculated for C.sub.19 H.sub.20 N.sub.3 O.sub.5 Cl.0.75 H.sub.2 O: C,
54.4; H, 5.0; N, 10.0. Found: C, 54.5H, 5.3; N, 9.5%.
The starting material was prepared as follows:
i) To a vigorously stirred mixture of piperazinone (3.23 g), potassium
carbonate (4.46 g) in water (15 ml) and tert-butanol (15 ml) at room
temperature, was added portionwise over 5 minutes, di tert-butyl
dicarbonate (7.75 g). The mixture was stirred for 2 hours. Ethyl acetate
(20 ml) was added to extract the solid thus formed and the organic layer
separated, filtered through phase separating paper and evaporated. The
solid residue recrystallised from ethyl acetate to give
4-tert-butoxycarbonylpiperazin-2-one (5.31 g), m.p.
157.degree.-159.degree. C.; NMR (d.sub.6 DMSO) .delta. 8.0(1H,br),
3.81(2H,s), 3.45(2H,t), 3.17(2H,m), 1.4(9H,s); m/e 207 (M+H).sup.+.
ii) To a stirred suspension of the product of step i) (0.5 g) in dry DMF (3
ml) under an argon atmosphere, was added sodium hydride (60% dispersion in
mineral oil, 0.1 g). After 1 hour at room temperature, methyl
4-bromoacetylphenoxyacetate (0.72 g) was added and the solution stirred
for 11/2 hours. The mixture resulting was partitioned between water and
ethyl acetate. The organic layer was separated, washed with water and
filtered through phase separating phase. Evaporation of the solvent gave
an oil which was purified by flash column chromatography, the product
being eluted with 1/1 v:v ethyl acetate/hexane to give methyl
4-(2-(4-tert-butoxycarbonyl)piperazin-2-one-1-yl!acetyl)phenoxyacetate as
a solid (0.32 g), m.p. 81.degree.-82.degree. C.; NMR (CDCl.sub.3) .delta.
7.97(2H,m), 6.98(2H,m), 4.83(2H,s), 4.71(2H,s), 4.18(2H,s), 3.81(3H,s),
3.72(2H,t), 3.42(2H,t), 1.47(9H,s).
iii) A solution of the product from step ii) (2.2 g) in TFA (10 ml) was
kept at room temperature for 1 hour and then evaporated to dryness. The
residue was partitioned between ethyl acetate and aqueous sodium
carbonate. The organic layer was filtered through phase separating paper
and solvent evaporated. The residue was triturated with ethyl acetate to
give a solid, m.p. 128.degree.-132.degree. C. NMR (d.sub.6 DMSO) .delta.
7.95(2H, d), 7.06(2H,d), 4.9(2H,s), 3.7(3H,s), 3.3(2H,m), 2.9(2H,m).
EXAMPLE 203
RS 3-Methyl-4-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyric acid
trifluoroacetate
To a stirred suspension of 4-4-(4-pyridyl)piperazin-1-yl!phenol (1.02 g)
in dry DMF (10 ml) was added solution hydride (60% dispersion in mineral
oil, 0.16 g) and the mixture stirred for 1 hour at room temperature. To
the resulting solution was added ethyl-4-bromo-3-methylbutyrate and the
mixture stirred for 16 hours. Solvent was evaporated and the residue
partitioned between water and dichloromethane. Insoluble material was
removed by centrifugation. The organic layer was filtered through phase
separating paper (Whatman IPS) and the residue was purified by flash
chromatography on silica gel by elution with
methanol/dichloromethane/concentrated ammonia (50/950/5) to give ethyl
3-methyl-4-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyrate (0.27 g) which
was hydrolysed in methanol (3 ml) and aqueous sodium hydroxide (1N, 2 ml)
for 2 hours at room temperature. The solution was evaporated and the
residue purified by reverse phase h.p.l.c (water/acetonitrile/0.1% TFA
gradient) to give a glass which crystallised on trituration with ether to
give the title compound (0.08 g): m.p. 169.degree.-171.degree. C.; NMR
(d.sub.6 DMSO) .delta. 13.45(1H,br), 12.07 (1H,br), 8.27(2H,d),
7.28(2H,d), 6.9(4H,m), 3.80(6H,m), 3.16(4H,t), 2.45(1H,m), 2.37(1H,m),
2.12(1H,m), 1.0(3H,d); m/e 356(M+H).sup.+ ; calculated for C.sub.22
H.sub.25 N.sub.3 O.sub.4 F.sub.3. 0.5 H.sub.2 O: C, 55.2; H, 5.6; N, 8.9
Found: C, 55.3; H, 5.6; N, 8.7%.
EXAMPLE 204
RS-4-4-4-(4-Pyridyl)piperazin-1-yl!phenoxy!-3-vinylbutyric acid, sodium
salt
A solution of RS methyl
4-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!-3-vinylbutyrate (0.29 g) in 1N
sodium hydroxide solution (2.3 ml) and methanol (5 ml) was kept at room
temperature for 4 hours. The solution was evaporated and water (2 ml)
added to the solid residue. The solid thus obtained was filtered and
washed with acetone and ether to give the title compound (0.042 g): m.p.
293.degree.-295.degree. C.; NMR (d.sub.6 DMSO) .delta. 8.18(2H,d),
6.9(6H,m), 5.88(1H,m), 4.96(2H,m), 4.0(1H,m), 3.77(1H,t), 3.41(2H,m),
3.10(2H,m), 2.84(1H,m), 1.98(2H,d), m/e 470(M+H).sup.+ ; calculated for
C.sub.21 H.sub.24 N.sub.3 O.sub.3 Na. H.sub.2 O: C, 61.9; H, 6.4; N, 10.3.
Found: C, 62.1; H, 6.4; N, 10.5%.
The starting material was prepared as follows:
i) A solution of RS 3-vinylbutyrolactone (3.5 g) and sodium acetate (2.56
g) in methanol (30 ml) was kept for 20 hours. Solvent was evaporated and
the residue was partitioned between water and ether. The aqueous layer was
extracted twice more with ether and the extracts combined, filtered
through phase separating paper and evaporated. The residue was purified by
filtration chromatography on silica gel (Merck 7736) starting with 1/9
ethyl acetate/hexane and progressing to 4/6 ethyl acetate/hexane as eluent
to give methyl 4-hydroxy-3-vinylbutyrate as an oil; NMR (CDCl.sub.3)
.delta. 5.73(1H,m), 5.15(2H,m), 3.68(3H,s), 3.60(2H,t), 2.76(1H,m),
2.48(2H,m), 1.69(1H,t);; m/e 145(M+H).sup.+.
ii) To stirred suspension of 4-4-4-(4-pyridyl)piperazin-1-yl!phenol (1.98
g) in dichloromethane (30 ml) at 15.degree. C. was added
triphenylphosphine (2.04 g) followed by dropwise addition of diethyl
azodicaboxylate (1.35 g). The mixture was stirred until complete solution
was obtained. Methyl-4-hydroxy-3-vinylbutyrate (1.2 g) was added drowise
and the mixture stirred for 4 hours. The solid which had precipitated
during the reaction was the starting phenol and was filtered off. The
filtrate was evaporated and the residue treated with ethyl acetate (20 ml)
and filtered. The filtrate was extracted with 2N hydrochloric acid
(2.times.10 ml) and the aqueous layer separated and basified with 0.89
S.G. ammoniium hydroxide. The precipitate was extracted twice into ethyl
acetate and the combined extracts filtered through phase separating paper
and evaporated. The residue was purified by flash chromatography on silica
gel, eluting with methanol/dichloromethane/0.89 S.G. ammonium hydroxide
v:v:v 7.5/92.5/0.75 to give RS methyl
4-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!-3-vinylbutyrate (0.29 g); NMR
(CDCl.sub.3) .delta. 8.3(2H,d), 6.88(4H,m), 6.70(2H,d), 5.85(1H,m),
5.20(2H,m), 3.90(2H,m), 3.67(3H,s), 3.48(2H,m), 3.18(2H,m), 3.06(1H,m),
2.68(1H,m), 2.47(1H,m), 1.80(1H,br); m/e 382 (M+H).sup.+.
EXAMPLE 205
Ethyl 4-2-allyl-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyrate
In a similar manner to Example 50 but starting from
2-allyl-4-4-(4-pyridyl)piperazin-1-yl!phenol, the title compound was
prepared in 50% yield as a solid, m.p. 53.degree.-55.degree. C. NMR
(CDCl.sub.3) .delta. 8.3(2H,d), 6.83(1H,m), 6.79(2H,d), 6.71(2H,d.d),
6.0(1H,m), 5.1(2H,m), 4.15(2H,q), 3.98(2H,t), 3.49(4H,m), 3.39(2H,d),
3.19(4H,m), 2.53(2H,t), 2.11(2H,q), 1.76(3H,t), m/e 410(M+H).sup.+ ;
calculated for C.sub.24 H.sub.31 N.sub.3 O.sub.3.0.5 H.sub.2 O: C, 68.9;
H, 7.7; N, 10.0. Found: C, 68.8; H, 7.7; N, 9.9%.
The starting material was prepared as follows:
i) Sodium hydride (60% dispersion in mineral oil, 0.4 g) was added to a
stirred suspension of 4-4-(4-piperazin-1-yl!phenol (2.55 g) in DMF (25
ml) and the mixture stirred for 20 minutes at room temperature. Allyl
chloride (0.756 g) was added dropwise and stirring continued for 20 hours.
Ice-water (75 ml) was added and the mixture extracted three times with
ethyl acetate. The combined extracts were washed with water and brine,
dried (MgSO.sub.4) and evaporated. The residue was triturated with hexane
and filtered to give 4-4-(4-pyridyl)piperazin-1-yl!phenol allyl ether
(2.5 g) as a solid; NMR (d.sub.6 DMSO) .delta. 8.18(2H,dd), 6.8-7.0(6H,m),
5.92-6.13(1H,m), 5.2-5.45(2H,m), 4.5(2H,m), 3.45(4H,m), 3.11(4H,m).
ii) The product from step i) (5 g) was heated under argon in gently
refluxing diphenyl ether (15 g) for 21/2 hours. The mixture was cooled to
room temperature and ether (70 ml) was added. The solid material was
filtered and purified by flash chromatography on silica gel, eluting with
methanol/dichloromethane (1/4 v/v) to give
2-allyl-4-(4-pyridyl)piperazin-1-yl!phenol (0.88 g) as a solid, m.p.
180.degree.-182.degree. C.; NMR (d.sub.6 DMSO) .delta. 8.88(1H,s),
8.19(2H,dd), 6.87(2H,dd), 6.7(3H,m), 5.88-6.03(1H,m), 3.44(4H,t),
3.28(2H,d), 3.05(4H,t); m/e 296 (M+H).sup.+.
EXAMPLE 206
4-2-Allyl-4-4-pyridyl)piperazin-1-yl!phenoxy!butyric acid
In a similar manner to Example 51, but starting from the product of Example
205, the title compound was prepared as solid in 61% yield; m.p.
209.degree.-210.degree. C. (dec); NMR (d.sub.6 DMSO) .delta. 8.19(2H,d),
6.84(5H,m), 5.82-6.08(1H,m), 4.92-5.12(2H,m), 3.91(2H,t), 3.44(4H,t),
3.3(2H,d), 3.1(4H,t), 2.4(2H,t), 1.93(2H,t); m/e 382 (M+H).sup.+ ;
calculated for C.sub.22 H.sub.27 N.sub.3 O.sub.3 : C, 69.3; H, 7.13; N,
11.0. Found: C, 69.2; H, 7.3; N, 11.2%.
EXAMPLE 207
Ethyl 4-2-n-propyl-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyrate
In a similar manner to Example 50, but starting from
2-n-propyl-4-4-(4-pyridyl)piperazin-1-yl!phenol, the title compound was
prepared in 24% yield as a solid, m.p. 65.degree.-67.degree. C.; NMR
(CDCl.sub.3) .delta. 8.29(1H,d), 6.8(1H,d), 6.73(2H,d), 6.7(2H,d),
4.13(2H,q), 3.94(2H,t), 3.46(4H,t), 3.18(4H,t), 2.52(4H,m), 2.09(2H,m),
1.54(2H,m), 1.24(3H,t), 0.94(3H,t); m/e 412(M+H).sup.+.
The starting material was prepared as follows:
The product from Example 205ii) (0.74 g) in ethanol (25 ml) and 1N
hydrochloric acid (2.5 ml) was hydrogenated at room temperature and
atmospheric pressure over 10% palladium charcoal (0.15 g) until uptake of
hydrogen was complete. Catalyst was removed by filtration through
diatomaceous earth and the filtrate evaporated. The residue was trituratee
with a mixture of ethyl acetate (25 ml) and saturated sodium bicarbonate
solution (25 ml) and the insoluble solid was filtered and washed with
water and ethyl acetate. The aqueous layer of the filtrate was extracted
twice with dichloromethane and the combined organic extracts evaporated.
The residue was combined with the ethyl acetate-insoluble material and
treated with boiling ethanol (40 ml), unsoluble material being removed by
filtration. Evaporation of the filtrate gave
2-n-propyl-4-4-(4-pyridyl)piperazin-1-yl!phenol (0.7 g) as a solid NMR
(d.sub.6 DMSO) .delta. 8.84-8.68 (1H,m), 8.18(2H,d), 6.82 (2H,m),
6.7(3H,m), 4.1(1H,m), 3.42(4H,t), 3.17(3H,s), 3.05(4H,t), 2.48(DMSO),
1.55(2H,m), 0.89(3H,t).
EXAMPLE 208
4-2-n-Propyl4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyric acid
In a similar manner to Example 51, but starting from the product of Example
207 was prepared the title compound in 64% yield; m.p.
207.degree.-209.degree. C. (from isopropanol); NMR (d.sub.6 DMSO) .delta.
8.18(2H,d), 6.7-6.92(5H,m), 3.91(2H,t), 3.45(4H,t), 3.10 (4H,t),
2.5(DMSO), 2.4(2H,t), 1.91(2H,?), 1.54(2H,m), 0.9(3H,t),+isopropanol (0.69
mole %) at 3.79 and 1.04; m/e 384(M+H).sup.+. Calculated for C.sub.22
H.sub.29 N.sub.3 O.sub.3. 0.7C.sub.3 H.sub.7 O: C, 68.0; H, 8.2; N, 9.9.
Found C, 68.1; H, 8.2; N, 9.9%.
EXAMPLE 209
Ethyl 4-2-methyl-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyrate
In a similar manner to Example 50, but starting from
2-methyl-4-4-(4-pyridyl)piperazin-1-yl!phenol dihydrochloride was
prepared the title compound in 29% yield as a gum; NMR (CDCl.sub.3)
.delta. 8.3(2H,m), 6.45-6.35(5H,m), 4.14(2H,q), 3.87(2H,t), 3.14(4H,m),
2.53(2H,t), 2.21(3H,s), 2.11(2H,m), 1.24(3H,t); m/e 384(M+H).sup.+.
The starting material was prepared as follows:
i) Carbonyl dimidazole (5 g) was added portionwise to a stirred suspension
of N-benzyliminodiacetic acid (3.14 g) in dry THF (50 ml) at room
temperature under argon. After 5 minutes, the mixture was heated at gentle
reflux for 15 minutes and (4-amino-2-methyl)phenylbenzylether (3.0 g)
added and the mixture stirred at reflux for 17 hours. Solvent was
evaporated and the residue was stirred with ethyl acetate (100 ml) and
water (150 ml) for 11/2 hours. The solid was filtered, washed with water
and dried to give
4-4-benzyl-2,6-diketopiperazin-1-yl!-2-methylphenylbenzylether (4.7 g);
m.p. 118.degree.-126.degree. C. (dec); NMR (CDCl.sub.3) .delta.
7.1-7.32(10H, m), 6.78(3H,s), 4.93(2H,s), 3.56(2H,s), 3.4(4H,s),
2.12(3H,s); m/e 373(M+H).sup.+.
ii) To a solution of the product of step i) (2.9 g) in dry THF (50 ml) was
added lithium aluminium hydride (0.6 g) and the mixture heated at reflux
for 11/2 hours. The mixture was allowed to cool and more (0.3 g) lithium
aluminium hydride added and reflux continued for a further 11/2 hours. The
mixture was cooled and water (0.9 ml) added followed by sodium hydroxide
solution (1N, 3.6 ml) and the mixture refluxed for 10 minutes. The solid
was filtered and washed with THF. The filtrate and washings were
evaporated and the residue purified by flash chromatography on silica gel,
eluting with 5% ethyl acetate in dichloromethane increasing to 25% ethyl
acetate. Thus was obtained
2-methyl-4-{4-(benzyl)piperazin-1-yl}!phenylbenzyl ether as a solid (1
g); m.p. 118.degree.-120.degree. C.; NMR (CDCl.sub.3) .delta.
7.2-7.5(10H,m), 6.82(1H,d), 6.80(1H,d), 6.7(1H,m), 5.01(2H,s), 3.1(4H,m),
2.53(3H,s); m/e 373(M+H).sup.+.
iii) A suspension of the product of step ii) (1 g) in 1,2-dichloroethane
(25 ml) was cooled in ice-water and treated with
1-chloroethylchloroformate (0.77 g). The mixture was allows to warm to
room temperature, stirred for 30 minutes and heated at reflux for 30
minutes. Methanol (20 ml) was added and the mixture refluxed again for 30
minutes and evaporated. The residue was triturated with ether and
filtered. The solid was washed with ether and dried to give
2-methyl-4-piperazin-1-yl!!phenylbenzylether hydrochloride (0.95 g);
m.p. 195.degree.-198.degree. C.; NMR (d.sub.6 DMSO) .delta. 9.44(2H,bs),
7.3-7.5(6H,m), 6.98(2H,m), 5.08(?,s), 4.98(4H,bs), 3.38(4H,d), 2.2(3H,s);
m/e 281 (M+H).sup.+.
iv) A mixture of the product of step iii) (0.95 g), 4-chloropyridine
hydrochloride (0.46 g) and triethylamine (0.615 g) in water (10 ml) was
heated at 100.degree. C. for 3 hours. More 4-chloropyridine (0.34 g) and
triethylamine (0.3 ml) was added and reflux continued for a further 3
hours. The solution was cooled and extracted with dichloromethane
(2.times.15 ml). The organic layer was evaporated and the residue was
purified by flash chromatography on silica gel, eluting with 5% methanol
in dichloromethane, containing 0.4% concentrated ammonia, to give
2-methyl-4-4-(4-pyridyl)piperazin-1-yl!!phenylbenzyl ether (0.26 g); as
a solid; NMR (d.sub.6 DMSO) .delta. 8.19(2H,d), 7.25-7.5(5H,m),
6.88(4H,m), 6.74(1H,m), 5.03(2H,s), 3.44(4H,bt), 3.1(4H,bt), 2.18(3H,s);
m/e 360 (M+H).sup.+.
v) A solution of the product of step iv) (0.52 g) in ethanol (20 ml )
containing 2N hydrochloric acid (2 ml) was stirred with 10%
palladium/carbon (0.16 g) under an atmosphere of hydrogen until hydrogen
uptake was complete. The mixture was filtered and the filtrate evaporated.
The residue was triturated with hot ethyl acetate and filtered to give, as
a solid, 2-methyl-4-4-(4-pyridyl)piperazin-1-yl!phenol dihydrochloride
(0.55 g); NMR (d.sub.6 DMSO) .delta. 8.25(2H,d), 7.24(2H,d), 7.12(2H,bd),
6.8(1H,d), 4.02 3.46(4H,m), (4H,m), 2.1(3H,s); m/e 270(M+H).sup.+.
EXAMPLE 210
4-2-Methyl-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!-butyric acid
In a similar manner to Example 51, but starting from the product of Example
209, the title compound was obtained in 80% yield as a solid, m.p.
261.degree.-262.degree. C.; NMR (d.sub.6 DMSO) .delta. 8.18(2H,d),
6.7-6.9(2H,m), 3.9(2H,t), 3.43(4H,bt), 3.1(4H,bt), 2.39(2H,t), 2.13(3H,s),
1.72(2H,m; m/e 356(M+H).sup.+. Calculated for C.sub.20 H.sub.25 N.sub.3
O.sub.3 : C, 67.6, H, 7.1; N, 11.8. Found: C, 67.4; H, 6.9; N, 12.2%.
EXAMPLE 211
RS Methyl
2-t-butoxycarbonylamino-4-4-4-(4-pyridyl)piperazine-1-yl!phenoxy!butyrat
In a similar manner to Example 50, but starting from RS methyl
4-bromo-2-t-butoxycarbonylaminobutyrate, the title compound was prepared
in 65% yield as an oil; NMR (CDCl.sub.3) .delta. 8.31(2H,d), 6.9(4H,m),
6.71(2H,m), 5.3(1H,br), 4.5(1H,bd), 4.01(2H,t), 3.77(3H,s), 3.5(4H,m),
3.21(4H,m), 2.3(2H,m), 1.46(9H,s); also signals at 6.03, 2.97 and 2.9(DMF)
and 1.8(H.sub.2 O); m/e 471 (M+H).sup.+. Calculated for C.sub.25 H.sub.34
N.sub.4 O.sub.5. 0.5DMF. 0.5H.sub.2 O: C, 61.7; H, 7.5; N, 12.2. Found: C,
61.8; H, 7.2; N, 11.9%.
The starting material was prepared as follows:
i) A solution of RS-methyl-N-butoxycarbonyl homoserinate (1.7 g) and carbon
tetrabromide (3.6 g) in dichloromethane (20 ml) was stirred at 5.degree.
C. Triphenylphosphine (3.77 g) was added portionwise over 5 minutes. After
2 hours at room temperature the dark solution was evaporated and the
residue triturated with ether/hexane (1/1, 30 ml) until a solid was
obtained. The solid was filtered and the filtrate evaporated. The residue
was purified by flash chromatography, the product being eluted with 25%
ethyl acetate/hexane to give RS methyl
4-bromo-2-butyloxycarbonylaminobutyrate (0.41 g) as an oil; NMR
(CDCl.sub.3) .delta. 5.16(1H,br), 4.45(1H,m), 3.8(3H,s), 3.45(2H,t),
2.52-2.11(2H,m), 1.48(9H,s); m/e 296 (M+H).sup.+.
EXAMPLE 212
RS
2-t-Butoxycarbonylamino-4-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyric
acid
In a similar manner to Example 51, but starting from the compound of
Example 211, there was obtained in 58% yield, the title compound as a
solid; m.p. 198.degree.-207.degree. C.; NMR (d.sub.6 DMSO) .delta.
8.2(2H,d), 6.91(6H,m), 4.06(1H,m), 3.92(2H,t), 3.48(4H,t), 3.12(4H,t),
2.2-1.84(2H,m), 1.37(9H,s); m/e 457(M+H).sup.+. Calculated for C.sub.24
H.sub.32 N.sub.4 O.sub.5.H.sub.2 O: C, 60.7; H, 7.2; N, 11.8. Found: C,
60.7; H, 7.2; N, 11.7%.
EXAMPLE 213
RS Methyl 2-amino-4-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyrate
The compound of Example 211 (0.96 g) in TFA (10 ml) was kept at room
temperature for 2 hours. The solution was evaporated and the residue
dissolved in water (15 ml) and the solution basified with sodium
carbonate. The mixture was extracted three times with dichloromethane.
Evaporation of the combined extracts gave the title compound (0.56 g);
m.p. 125.degree.-127.degree. C.; NMR (d.sub.6 DMSO) .delta. 8.2(2H,d),
6.92(6H,m), 4.0(2H,m), 3.64(3H,s), 3.46(4H,t), 3.15(4H,t), 2.04(2H,m),
1.84(1H,m); m/e 371(M+H).sup.+. Calculated for C.sub.20 H.sub.26 N.sub.4
O.sub.3. 0.75 H.sub.2 O; C, 62.5; H, 7.17; N, 14.6. Found: C, 62.8; H,
6.8; N, 14.3%.
EXAMPLE 214
4-2-4-(4-Pyridyl)piperazin-2-one-1-yl!acetyl!phenoxyacetic acid, sodium
salt
The title compound of Example 61 (0.25 g) in methanol (5 ml) was treated
with aqueous sodium hydroxide (1N, 0.65 ml) and the mixture kept at room
temperature for 6 hours. The solid thus formed was filtered and washed
with methanol to give the title compound (0.18 g); m.p.
317.degree.-318.degree. C.; NMR (d.sub.6 DMSO) .delta. 8.2(2H,d),
7.89(2H,d), 6.91(2H,d), 6.83(2H,d), 4.89(2H,s), 4.21(2H,s), 4.01(2H,s),
3.68(2H,m), 3.51(2H,m); m/e 392(M+H).sup.+ ; calculated for C.sub.19
H.sub.18 N.sub.3 O.sub.5 Na. 0.25H.sub.2 O: C, 57.6; H, 4.6; N, 10. Found:
C, 57.2; H, 4.6; N, 10.4%.
EXAMPLE 215
Ethyl 4-2-4-(4-pyridyl)piperazin-2-one-1-yl!acetyl!phenoxyacetate
A crude sample of the product of Example 62 (3.4 g) was treated with a
solution, at 0.degree. C., made by adding thionyl chloride (2.25 g)
dropwise to ethanol (45 ml) with stirring at below 0.degree. C. The
mixture was stirred at room temperature for 2 hours, heated at gentle
reflux for 21/2 hours, and evaporated. The residue was treated with water
and adjusted to pH6 with aqueous sodium bicarbonate solution. The gum
which precipitated was separated and the aqueous solution was adjusted to
pH8 and extracted with dichloromethane (2.times.50 ml). The combined
extracts were washed with brine, dried and evaporated. The residue was
purified by chromatography using a 10 g. Mega Bond Elut silica gel column,
eluting with 5% methanol/dichloromethane/0.5% triethylamine to give the
title product as a solid (0.2 g); m.p. 163.degree.-165.degree. C.; NMR
(CDCl.sub.3) .delta. 8.34(2H,m), 6.98(2H,m)(, 6.63(2H,m), 4.89(2H,s),
4.7(2H,s), 4.29(2H,q), 4.1(2H,s), 3.7(2H,m), 3.6(2H,m), 1.31(3H,t); m/e
398(M+H).sup.+ ; calculated for C.sub.21 H.sub.23 N.sub.3 O.sub.5 : C,
63.5; M, 5.83; N, 10.6. Found: C, 61.5; H, 5.9; N, 10.5%.
EXAMPLE 216
Ethyl N
4-2-(4-(4-pyridyl)piperazin-2-one-1-yl)acetyl!phenoxyacetylglycinate
The compound of Example 62 (0.37 g) was stirred in DMF (10 ml) with
hydroxybenzotriazole (0.17 g) and the mixture cooled in ice-water.
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.14 g) was
added, followed by triethylamine (0.14 ml) and the mixture stirred for 30
minutes. Glycine ethyl ester hydrochloride (0.15 g) was now added,
followed by triethylamine (0.28 ml). After ten minutes stirring in the
cold, the mixture was allowed to warm to room temperature, stirred for two
days and evaporated. Water (10 ml) was added to the residue and sodium
bicarbonate added to pH 6-7. The mixture was evaporated and the residue
purified by chromatography on a Mega Bond Elut silica gel column (10 g),
eluting with 2%-20% methanol/dichloromethane. The product was
recrystallised from ethanol to give the title compound as a solid (36 mg);
m.p. 209.degree.-211.degree. C.; NMR (d.sub.6 DMSO) .delta. 8.55(1H,t),
8.2(2H,brd), 7.99(2H,m), 7.12(2H,m), 6.86(2H,d), 4.92(2H,s), 4.11(2H,q),
4.02(2H,s), 3.9(2H,d), 3.2(2H,m), 3.52(2H,m), 1.2(3H,t); m/e 455(M+H);
calculated for C.sub.23 H.sub.26 N.sub.4 O.sub.6 : C, 60.8; H, 5.77; N,
12.3. Found: C, 60.6; H, 5.7; N, 12.5%.
EXAMPLE 217
Ethyl 4-2-nitro-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyrate
Sulphur acid (98%, 2.5 ml) was added slowly to the compound of Example 50
(1 g) with stirring at room temperature. The solution was cooled to below
5.degree. C. and a mixture of nitric acid (0.18 ml) and sulphuric acid
(0.18 ml) was added dropwise. The solution was stirred at below 10.degree.
C. for 11/2 hours, poured onto ice and basified with ammonia solution to
pH10. The mixture was extracted with ethyl acetate (2.times.50 ml) and the
extract washed with water, dried (MgSO.sub.4) and evaporated. The residue
was purified by flash chromatography on silica gel, the product being
eluted with 5%-10% methanol/dichloromethane to give the title product as
an oil (0.18 g); NMR (CDCl.sub.3) .delta. 8.32(2H,d), 7.41(1H,d),
7.14(1H,m), 7.04(1H,d), 6.77(2H,m), 4.17-4.14(4H,m), 3.51-3.28 (8H,m),
2.57(2H,t), 2.14(2H,m), 1.28(3H,t), plus H.sub.2 O (1.87); m/e
415(M+H).sup.+ ; calculated for C.sub.21 H.sub.26 N.sub.4
O.sub.5.0.25H.sub.2 O: C, 60.1; H,6.3; N, 13.1. Found: C, 60.2; H, 6.3; N
13.2%.
EXAMPLE 218
RS Methyl
2-n-butanesulphonylamino-4-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyrat
e
n-Butanesulphonychloride (0.233 g) was added to a stirred solution of the
compound of Example 213 (0.5 g) and triethylamine (0.15 g) in
dichloromethane (15 ml) at room temperature. The solution was kept for 2
days and subjected to flash column chromatography on silica gel. The
product was kept for 2 days and subjected to flash column chromatography
on silica gel. The product was eluted with methanol/dichloromethane/0.88SG
ammonia (7/93/0.7) v:v:v to give, after trituration with ether, the title
compound in 58% yield as a solid; m.p. 124.degree.-125.degree. C.; NMR
(CDCl.sub.3) .delta. 8.3(2H,d), 6.88(4H,q), 6.72(2H,m), 5.18(1H,brd),
4.16(1H,brq), 4.08(2H,t), 3.8(3H,s), 3.47(4H,m(, 3.18(4H,m), 2.98(2H,m),
2.28(2H,m), 1.73(2H,m), 1.45-1.27(2H,m), 0.9(3H,t); m/e 491 (M+H).sup.+ ;
calculated for C.sub.24 H.sub.34 N.sub.4 O.sub.5 S: C, 58.8; H, 7.0; N,
11.4. Found: C, 58.4; H, 7.0; N, 11.1%.
EXAMPLE 219
RS
2-n-Butanesulphonylamino-4-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyric
acid
In a similar manner to Example 51, but starting from the compound of
Example 218, was prepared the titled compound in 58% yield as a solid;
m.p. 251.degree.-252.degree. C.; NMR (d.sub.6 DMSO) .delta. 8.18(2H,d),
7.3(1H,vbr), 6.9(6H,m), 3.97(2H,t), 3.9(1H,m), 3.45(4H,t), 3.11(4H,t),
2.9(2H,t), 2.12(1H,m), 1.92(1H,m), 1.58(2H,m), 0.81(3H,t); m/e
477(M+H).sup.+ ; calculated for C.sub.23 H.sub.32 N.sub.4 O.sub.5 S. 0.5
H.sub.2 O: C, 56.9; H, 6.8; N, 11.5. Found: C,57.0; H, 6.8; N, 11.3%.
EXAMPLE 220
RS 3-Benzyl-4-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!-butyric acid
In a similar manner to Example 51,but starting from RS ethyl
3-benzyl-4-4-(4-pyridyl)piperazin-1-yl!phenoxybutyrate, was prepared the
title compound in 65% yield as a solid; m.p. 205.degree.-206.degree. C.;
NMR (d.sub.6 DMSO) .delta. 8.2(2H,d), 7.22(5H,m), 6.9(6H,m), 3.8(2H,d),
3.45(4H,m), 3.15(4H,m), 2.72(2H,m), 2.5-2.18(Me.sub.2 SO+3H,m); m/e
432(M+H).sup.+ ; calculated for C.sub.26 H.sub.29 N.sub.3
O.sub.3.0.25H.sub.2 O: C, 71.6; H, 6.8; N, 9.7. Found: C, 71.9; H, 6.8; N,
9.5%.
The starting material was prepared as follows:
i) A solution of RS 3-benzylbutyrolactone (1.14 g) in ethanol (20 ml) was
stirred at 5.degree. C. and gassed for 4 hours with a slow stream of
hydrogen bromide. The solution was kept at 5.degree. C. for 20 hours and
water (70 ml) added followed by sodium carbonate to neutralise the acid.
The mixture was extracted with ethyl acetate and the organic layer
filtered through phase separating paper and evaporated to give ethyl
4-benzyl-3-bromobutyrate as an oil; NMR (CDCl.sub.3) .delta. 7.24(5H,m),
4.13(2H,q); 3.45(2H,m), 2.62(2H,d), 2.44(3H,m), 1.25(3H,t); m/e
285(M+H).sup.+.
ii) In a similar manner to Example 50 ,but starting from the product of
step i) was prepared RS ethyl
3-benzyl-4-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyrate in 40% yield
as an oil; NMR (CDCl.sub.3) .delta. 8.34(2H,d), 7.29(5H,m), 6.9(4H,m),
6.72(2H,m), 5.13(2H,q), 3.85(2H,m), 3.5(4H,m), 3.3(4H,m), 2.9-2.38(5H,m),
1.26(3H,t); m/e 460(M+H).sup.+.
EXAMPLE 221
RS 3-Phenyl-4-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!-butyric acid
In a similar manner to Example 51, but starting from RS methyl
3-phenyl-4-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyrate, was prepared
the title compound in 39% yield as a solid; m.p. 120.degree.-125.degree.
C.; NMR (d.sub.6 DMSO) .delta. 8.18(2H,d), 7.32(5H,m), 7.25(2H,d),
6.87(6H,m), 4.04(2H,q), 3.45(5H,m), 3.11(4H,t), 2.71(2H,m); m/e
418(M+H).sup.+ ; calculated for C.sub.25 H.sub.27 N.sub.3 O.sub.3.
0.25H.sub.2 O: C, 7.1; H, 6.5; N,9.9. Found: C, 7.2; H, 6.5; N,9.8%.
The starting material was prepared as follows:
i) In a similar manner to Example 204ii), but starting from RS ethyl
4-hydroxy-3-phenylbutyrate was made RS
methyl-3-phenyl-4-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyrate in 10%
yield as an oil; NMR (d.sub.6 DMSO+CD.sub.3 COOD) .delta. 8.23(2H,d),
7.3(5H,m), 7.17(2H,d), 6.95(2H,d), 6.83(2H,d), 4.06(2H,m), 3.77(4H,t),
3.55(3H,s), 3.51(1H,m), 3.17(4H, t), 2.83(2H,m); m/e 432(M+H).sup.+.
EXAMPLE 222
N-1-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!piperidin-4-ylmethyl!-4-methylp
henylsulphonamide
A solution of
N-(1-bromoacetylpiperidin-4-ylmethyl)-4-methylphenylsulphonamide (1.0 g),
1-(4-pyridyl)piperazine (600 mg) and triethylamine (0.5 ml) in
acetonitrile (20 ml) was stirred for 1 hr and then left to stand
overnight. The solvent was evaporated in vacuo and the residue purified by
chromatography on silica, eluting with 5% v/v methanol/dichloromethane.
Evaporation of the eluant fractions gave a colourless solid (280 mg). The
title compound was obtained as colourless prisms (150 mg), m.p.
156.degree.-158.degree. C. (from ethyl acetate); NMR (d.sub.6 DMSO)
.delta. 0.8-1.2(2H,m); 1.5-1.8(3H,m); 2.35(3H,s); 2.4(6H,m); 2.6(2H,t);
2.8-3.0(1H,t); 3.2(1H,d); 3.2-3.5(4H,m); 4.0(1H,d); 4.3(1H,d); 6.8(2H,d);
7.4(2H,d), 7.55(1H,t); 7.7(2H,d); 8.2; (2H,d); m/e 472 (M+H).sup.+ ;
calculated for C.sub.24 H.sub.33 N.sub.5 O.sub.3 S: C,61.1; H,7.1;N,14.8;
found: C,60.9; N,7.1; N,14.5%.
The starting material was prepared as follows:
i) Sodium hydride (300 mg of a 60% suspension) was added to a stirred
solution of 4-methylphenylsulphonamide and the mixture stirred at room
temperature until effervescence had ceased.
N-benzyloxycarbonylpiperidine-4-methanol mesylate (1.09 g) was added and
the mixture heated at 100.degree. C. for 7 hours. After cooling to room
temperature it was diluted with water (200 ml) and extracted with ether
(4.times.40 ml); the extracts were combined, washed with water (2.times.)
and brine, dried (MgSO.sub.4) and evaporated to yield
N-(1-benzyloxycarbonylpiperidin-4-ylmethyl)-4-methylphenylsulphonamide;
NMR (d.sub.6 DMSO) .delta. 0.81-1.1(2H,m); 1.5-1.7(3H,m); 2.35(3H,s);
2.6(2H,t); 2.7-2.9(2H,m); 4.0(2H,d); 5.0(2H,s); 7.2-7.5(7H,m); 7.55(1H,t);
7.7(2H,d); m/e 403 (M+H).sup.+.
ii) To a solution of the product of step i) (1.2 g) in absolute ethanol (30
ml) was added 10% palladium-on-charcoal catalyst (200 mg) and the mixture
stirred in an atmosphere of hydrogen until all the starting material had
reacted (Tlc). After removal of the catalyst by filtration, the solvent
was evaporated in vacuo and the residue dried under high vacuum to yield
the free amine as a colourless gum (800 mg). This was dissolved in
dichloromethane, the solution stirred with ice-cooling and treated
sequentially with triethylamine (0.45 ml) and bromoacetyl bromide (0.3
ml). The mixture was stirred for 1 hr and then washed with water (25 ml)
and brine (25 ml), dried (PS paper) and evaporated in vacuo to yield crude
N-(1-bromoacetylpiperidin-4-ylmethyl)-4-methylphenylsulphonamide as a
colourless gum (1.0 g) which was used without further purification or
characterisation.
EXAMPLE 223
N-2-1-2-4-(4-pyridyl)piperazin-1-yl!acetyl!piperidin-4-ylethyl!-4-methy
lphenylsulphonamide, dihydrochloride
In a similar manner to Example 222, but starting from
N-2-(1-bromoacetyl-piperidin-4-ylethyl!-4-methylphenylsulphonamide, the
title compound was obtained as a dihydrochloride salt (160 mg colourless
prisms) containing 1/3 mole ethanol of crystallisation, m.p.
258.degree.-260.degree. C. (from ethanol); NMR (d.sub.6 DMSO+CD.sub.3
COOD) .delta. 0.8-1.2 (2H,m); 1.5-1.8(3H,m); 2.4(3H,s); 2.6(2H,m);
2.8(2H,t), 3.0(1H,t), 3.4-3.7(5H,m); 3.9-4.2(4H,m); 4.3-4.5(3H,m);
7.25(2H,d), 7.4(2H,d); 7.7(2H,d); m/e 486 (M+H).sup.+ ; calculated for
C.sub.25 H.sub.35 N.sub.5 O.sub.3 S.2HCl.0.33 EtOH: C,53.7; H,6.9; N,12.1;
found: C,53.5; H,7.0;N,12.3%.
The starting material was prepared as follows:
i) 4-Piperidine ethanol was reacted with benzyloxycarbonyl chloride in
triethylamine to yield (after chromatography)
1-benzyloxycarbonylpiperidin-4-ylethanol as a colourless oil. (2.0 g); NMR
(d.sub.6 DMSO) .delta. 0.9-1.2(2H,m); 1.2-1.4(2H,q); 1.5-1.8(3H,m);
2.6-2.9(2H,t); 3.45(2H,q); 4.0(2H,d); 4.35(1H,t); 5.1(2H,s); 7.35(5H,m);
m/e 264 (M+H).sup.+.
ii) A solution of methanesulphonyl chloride (0.85 ml) in dichloromethane
(20 ml) was added dropwise to a stirred, ice-cooled solution of
triethylamine (1.55 ml) and the product of step i) (2.64 g) in
dichloromethane (50 ml). After stirring for 3 hours the reaction mixture
was washed with water (3.times.) and brine, dried (PS paper) and
evaporated in vacuo to yield N-benzyloxycarbonylpiperidin-4-ylethanol
mesylate as a colourless paste (3.4 g) NMR (d.sub.6 DMSO) .delta.
0.9-1.2(2H,m); 1.5-1.8(5H,m); 2.6-2.9(2H,m); 4.0(2H,d); 4.25(2H,t);
4.4(3H,s); 5.1(2H,s); 7.35(5H,m); m/e 342 (M+H).sup.+.
iii) Following a method similar to that described in Example 222i), but
starting from the product of step ii) there was obtained
N-(1-benzyloxycarbonylpiperidin-4-ylethanol)-4-methylphenylsulphonamide as
a colourless gum (900 mg) after chromatography on alumina, NMR (d.sub.6
DMSO) .delta. 0.8-1.0 (2H,m); 1.3 (2H,q); 1.4-1.6 (3H,m); 2.4(3H,s);
2.6-2.8(4H,m); 4.0(2H,d); 5.1(2H,s); 7.2-7.4(7H,m); 7.5(1H,t); 7.7(2H,d);
m/e 417 (M+H).sup.+.
iv) In a similar manner to Example 222ii) but starting from the product of
step iii) there was obtained
N-(1-bromoacetylpiperidin-4-ylmethyl)-4-methylphenylsulphonamide as a pale
yellow gum (800 mg), NMR (CDCl.sub.3) .delta. 1.0-1.4(3H,m); 1.45(2H,q);
1.5-1.8(3H,m); 2.45(3H,s); 2.5-2.7(1H,m); 3.0(2H,m); 3.8(2H,m);
4.4-4.7(2H,m); 7.3(2H,d); 7.75(2H,d); m/e 403/405 (M+H).sup.+.
EXAMPLE 224
4-4-3-(4-dimethylaminopyrid-3-yl)propyloxy!phenoxy!butyric acid
To a solution of ethyl
4-4-3-(4-dimethylaminopyrid-3-yl)propyloxy!phenoxy!butyrate (160 mg) in
methanol (10 ml) was added sodium hydroxide solution (2.0 ml of 1.0M) and
the solution left until all starting ester had disappeared (Tlc). The
reaction mixture was neutralised with hydrochloric acid (2.0 ml) of 1.0M)
and evaporated in vacuo. A small amount (5 ml) of water was added and the
resulting solution extracted with dichloromethane (3.times.15 ml). The
organic extracts were combined, dried (PS paper) and evaporated to yield
the title compound as colourless prisms, (90 mg) m.p.
106.degree.-108.degree. C. (from ethyl acetate); NMR (d.sub.6 DMSO)
.delta. 1.8-2.1(2H,q;2H,q); 2.4(2H,t); 2.8(2H,t;6H,s); 3.9(2H,t;2H,t);
6.8(5H,m); 8.2(2H,d); m/e 359 (M+H).sup.+ ; calculated for C.sub.20
H.sub.26 N.sub.2 O.sub.4 : C,67.0;H,7.3;N, 7.8; found: C,67.1;H,7.6;N,
7.7%.
The starting material was prepared as follows:
i) A solution of 4-benzyloxyphenol (4.2 g) in dimethyl formamide (50 ml)
was treated with sodium hydride (840 mg) of a 60% dispersion), and the
mixture stirred until evolution of gas ceased. There was then added ethyl
3-bromobutyrate (2.9 ml), and the solution stirred overnight. It was then
poured into water (300 ml) and the mixture extracted with ether
(3.times.50 ml). The combined extracts were washed with water (3.times.)
and brine, dried (MgSO.sub.4) and evaporated to give a crude product as a
brown oil (6 g). This was purified by chromatography on silica, eluting
with hexane containing increasing amounts of ethyl acetate to give ethyl
3-(4-benzyloxyphenoxy)butyrate as a colourless crystalline solid (4.5 g)
NMR (d.sub.6 DMSO) .delta. 1.25(3H,t); 1.8-2.0(2H,m); 2.45(2H,t);
3.9(2H,t); 4.1(2H,q); 5.0(2H,s); 6.8-7.0(4H,m); 7.4(5H,m); m/e 314
(M+H).sup.+.
ii) To a solution of the product of step i) (4.5 g) in absolute ethanol
(200 ml) was added 10% palladium-on-charcoal catalyst (1.2 g) and the
resulting suspension hydrogenated at ambient temperature and pressure
until uptake of hydrogen ceased. The catalyst was removed by filtration
through celite and the filtrate was concentrated in vacuo to give ethyl
3-(4-hydroxyphenoxy)butyrate as a low-melting crystalline solid (3.0 g)
NMR (d.sub.6 DMSO) .delta. 1.25(3H,t); 1.8-2.0(2H,m); 2.5(2H,t);
3.9(2H,t); 4.1(2H,q); 6.7(4H,m); 8.8)1H,brs); m/e 224 (M).sup.+.
iii) A solution of 4-dimethylaminopyridine-3-aldehyde prepared according to
J. Het. Chem. 25 p81 (1988).(1.5 g) and ethyl triphenylphosphoranylidene
acetate (3.85 g) in acetonitrile (25 ml) was refluxed for seven hours. The
solvent was removed in vacuo and the residue dissolved in dilute
hydrochloric acid (30 ml of 1M); the solution was washed with ethyl
acetate (2.times.20 ml) and then basified with solid sodium hydrogen
carbonate. The resulting solution was extracted with dichloromethane
(3.times.20ml) and the combined extracts washed with brine, dried (PS
paper) and evaporated to yield the crude product as a brown oil (2.0 g).
This was purified by chromatography on silica, eluting with ethyl acetate,
to give ethyl 2-(4-dimethylamino-3-pyridyl)propenoate as a pale yellow oil
(1.5 g). NMR (d.sub.6 DMSO) .delta. 1.25(3H,t); 2.85(6H,s); 4.2(2H,q);
6.5(1H,d); 6.9(1H,d); 7.5(1H,d); 8.25(1H,d); 8.5(1H,s); m/e
221(M+H).sup.+.
iv) To a solution of the product of step iii) (3.6 g) in absolute ethanol
(100 ml) was added 5% palladium/charcoal catalyst, and the mixture
hydrogenated at ambient temperature and pressure until the theoretical
volume of hydrogen had been consumed. The catalyst was removed by
filtration through celite and the filtrate evaporated to yield ethyl
2-(4-dimethylamino-3-pyridyl)propanoate as a pale yellow oil (3,1 g) NMR
(d.sub.6 DMSO) .delta. 1.15(3H,t); 2.65(2H,t); 2.8(6H,s); 2.9(2H,t);
4.05(2H,q); 6.8(2H,d); 8.2(2H,d); m/e 223 (M+H).sup.+.
v) To a stirred solution of the product of step iv) (2.6 g) in
tetrahydrofuran (100 ml) was added lithium aluminium hydride (1.2 g) and
the resulting suspension stirred for 4 hours at ambient temperature.
Excess reducing agent was destroyed by the sequential addition of ethyl
acetate, water, and conc. HCl. The mixture was then basified and extracted
sequentially with ethyl acetate and dichloromethane. The organic extracts
were combined, dried (PS paper and MgSO.sub.4) and evaporated to yield
4-dimethylamino-3-(3-hydroxypropyl)pyridine as a pale yellow oil (2.2 g),
essentially pure by Tlc; NMR (d.sub.6 DMSO) .delta. 1.6-1.8(2H,m):
2.65(2H,t); 2.8(6H,s); 3.5(2H,t); 4.5(1H,brs); 6.7(2H,d); 8.2(2H,d); m/e
181 (M+H).sup.+.
vi) A solution of the product of step v) (600 mg), the product of step (ii)
(750 ml) and triphenylphosphine (920 mg) in tetrahydrofuran (20 ml) was
stirred at ambient temperature for 0.5 hr. To this was added
diethylazodicarboxylate (0.61 ml) and the resulting solution stirred for 1
hr. The solvent was evaporated and the residue purified by chromatography
on silica eluting with 2% v/v ethanol/dichloromethane. Evaporation of the
eluant fractions gave ethyl
4-4-3-(4-dimethylaminopyrid-3-yl)propyloxy!phenoy!butyrate as an orange
oil (450 mg); NMR (d.sub.6 DMSO+CD.sub.3 COOD) .delta. 1.1(3H,t);
1.8-2.0(2H,q;2H,q); 2.35(2H,t); 2.85(2H,t); 3.1(6H,s); 3.8(2H,t;2H,t);
4.0(2H,q); 6.7(4H,s); 6.9(1H,d); 8.0(2H,d); m/e 387 (M+H).sup.+.
EXAMPLE 225
2-S-(Benzyloxycarbonylamino-3-4-3-4-dimethylamino-pyrid-3-yl!propoxy!phe
nyl!propionic acid
In a similar manner to Example 224 but starting from methyl
2-S-(benzyloxy-carbonylamino)-3-4-3-4-dimethylaminopyrid-3-yl!propoxyph
enyl!propionate the crude title compound was prepared as a colourless foam
(200 mg). This was dissolved in distilled water (25 ml) containing dilute
hydrochloric acid (1.0 ml of 1M), the solution washed with ether
(2.times.10 ml), filtered and lyophilised to give the title compound as a
colourless solid (180 mg); NMR (d.sub.6 DMSO+CD.sub.3 COOD) .delta.
2.05(2H,m); 2.7-3.2(5H,m); 3.2(6H,s); 4.0(2H,t); 4.3(1H,q); 5.0(2H,s);
6.8(2H,d); 7.0(1H,d); 7.2(2H,d); 7.3(5 H,m); 8.1(2H,d; m/e 478 (M+H)+;
calculated for C.sub.27 H.sub.31 N.sub.3 O.sub.5.HCl.0.75 H.sub.2 O:
C,61.5;H,6.4;N,8.0;H.sub.2 O 2.5; found: C,61.6; H,6.6;N,7.8; H.sub.2 O
2.1%.
The starting material was prepared in a similar manner to Example 224 vi),
but starting from methyl
2-S-benzyloxycarbonylamino-3-(4-hydroxyphenyl)propionate, yielding a
colourless gum (1.0 g); NMR (d.sub.6 DMSO+CD.sub.3 COOD) .delta.
2.05(2H,m); 2.7-3.2(4H,m); 3.2(6H,s); 3.7(3H,s); 4.0(2H,t); 4.3(1H,q);
5.0(2H,s); 6.8(2H,d); 7.0(1H,d); 7.2(2H,d); 7.3(5H,m); 8.1(2H,d); m/e 492
(M+H).sup.+.
EXAMPLE 226
Ethyl 3-4-(4-pyridyl)piperazin-1-yl!phenoxybutyrate
In a similar manner to that described in Example 50, but starting from
3-4-(4-pyridyl)piperazin-1-yl!phenol, the title compound was prepared as
colourless prisms, 560 mg m.p. 160.degree.-162.degree. C. (from ethanol);
NMR (d.sub.6 DMSO) .delta. 1.2(3H,t); 185-2.05(2H,q); 2.45(2H,t);
3.4(4H,m); 3.85(4H,m); 4.0(2H,t); 4.1(2H,q); 6.45(1H,m); 6.65(2H,m);
7.15(1H,t); 7.25(2H,d); 8.2(2H,t); m/e 370 (M+H).sup.30 ; calculated for
C.sub.21 H.sub.27 N.sub.3 O.sub.3.2HCl. 0.6 H.sub.2 O: C,55.7; H,6.7;
N,9.3; H.sub.2 O,2.8; found: C,56.0; H,6.8;N,9.2; H.sub.2 O,3.0%.
The starting material was prepared as follows:
i) 3-4-(3-pyridyl)piperazin-1-yl)!anisole was prepared in a manner similar
to that described in Example 50, but starting from
3-(1-piperazinyl)anisole, giving yellow prisms (from carbon
tetrachloride), 4.8 g. NMR (d.sub.6 DMSO) .delta. 3.25(4H,m); 3.45(4H,m);
3.75(3H,s); 6.4(1H,m); 6.5(1H,m); 6.55(1H,m); 6.85(2H,d); 7.15(1H,t);
8.2(2H,d); m/e 270 (M+H).sup.+.
ii) 3-4-(4-pyridly)piperazin-1-yl!phenol was prepared in a similar manner
to that described in Example 50, but starting from
3-4-(4-pyridyl)piperazin-1yl!anisole to give the phenol as a pale brown
solid, (3.5 g) NMR (d.sub.6 DMSO) .delta. 3.3(4H,m); 3.6(4H,m);
6.35(1H,m); 6.5(2H,m); 7.0(2H,d); 7.15(1H,t); 8.3(2H,d); 9.0-9.5(1H,brs);
m/e 256 (M+H).sup.+.
EXAMPLE 227
3-4-(4-Pyridyl)piperazin-1-yl!phenoxybutyric acid
In a manner similar to that described in Example 51, but starting from the
product of Example 226, the title compound (180 mg) was obtained as pale
yellow prisms, m.p. 196.degree.-198.degree. C. (from water); NMR (d.sub.6
DMSO) .delta. 1.8-2.0(2H,q); 2.4(2H,t); 3.25(4H,m); 3.45(4H,m); 4.0(2H,t);
6.4(1H,m); 6.5(2H,m); 6.85(2H,m); 7.15(1H,t); 8.2(2H,d); m/e 342
(M+H).sup.+ ; calculated for C.sub.19 H.sub.23 N.sub.3 O.sub.3. 0.2
H.sub.2 O: C.6.61; H,6.8; N,12.2; H.sub.2 O,1.0; found: C,65.8; H,6.7;
N,12.1; H.sub.2 O,0.8%.
EXAMPLE 228
Ethyl 3-4-(4-pyridyl)piperazin-1-yl!phenoxypentanoate
Following the method of Example 226, title compound (340 mg) was obtained
as a colourless prisms, m.p. 62.degree.-64.degree.C. (from ethanol); NMR
(d.sub.6 DMSO) .delta. 1.2(3H,t); 1.6-1.8(4H,m); 2.35(2H,t); 3.25(4H,m);
3.45(4H,m); 3.95(2H,t); 4.05(2H,q); 6.4(1H,m); 6.5(1H,m); 6.55(1H,m;
6.85(2H,m); 7.15(1H,t); 8.2(2H,d); m/e 384 (M+H).sup.+ ; calculated for
C.sub.22 H.sub.29 N.sub.3 O.sub.3 : C,68.9, H,7.6; N.11.0; found: C,68.7;
H,7.8;N,11.0%.
EXAMPLE 229
3-4-(4-Pyridyl)piperazin-1-yl!phenoxypentanoic acid
Following the method of Example 227, the title compound (150 mg) was
obtained as a pale yellow prisms, m.p. 235.degree.-237.degree. C. (from
water); NMR (d.sub.6 DMSO) .delta. 1.55-1.85(4H,m); 2.3 (2H,t);
3.35(4H,m); 3.75(4H,m); 4.0(2H,t); 6.4(1H,m); 6.5(1H,m); 6.55(1H,m);
7.15(3H,m); 8.2(2H,d); m/e 356 (M+H).sup.+ ; calculated for C.sub.20
H.sub.25 N.sub.3 O.sub.3 :C,67.6; H,7.1;N,11.8; found: C,67; H,7.2;
N,11.8%.
EXAMPLE 230
Trans-methyl-4-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!cyclohexyl
carboxylate
To a mixture of 4-((4-pyridyl)piperazin-1-yl)phenol (860 mg), methyl
4-hydroxycyclohexane carboxylate (533 mg) and triphenylphosphine (884 mg)
in dry THF (50 ml), cooled to 5.degree. C., was added dropwise diethyl
azodicarboxylate (0.53 ml). The resulting mixture was stirred at room
temperature for 18 hours. The mixture was concentrated and purified by
flash column chromatography on silica, eluting with
methanol/dichloromethane (5.95 v/v) to give the title compound (178 mg)as
a solid; NMR (CDCl.sub.3) .delta. 1.4-1.65(4H,m), 2.05-2.1(2H,m),
2.15-2.2(2H,m), 2.3-2.4(1H,m), 3.15-3.2(4H,m), 3.45-3.5(4H,m), 3.7(3H,s),
4.05-4.15(1H,m), 6.7(2H,d), 6.85-6.95(4H,dd), 8.3(2H,d); m/e 396
(M+H).sup.+ ; calculated for C.sub.23 H.sub.29 N.sub.3 O.sub.3.0.5H.sub.2
O: c,68.3; H,7.4; N,10.4. Found: C,68.3; N,7.4; N,10.5%.
EXAMPLE 231
Trans-4-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!cyclohexane carboxylic acid
In a similar manner to Example 57 was prepared the title compound in 98%
yield as a solid; NMR (d.sub.6 DMSO+CF.sub.3 COOD) .delta.
1.35-1.65(4H,m), 1.95-2.15(4H,m), 2.2-2.35(1H,m), 3.6-3.75(4H,m),
4.05-4.2(4H,m), 4.25-4.4(1H,m), 7.05(2H,d); 7.35(2H,d). 7.45(2H,d),
8.35(2H,d); m/e 380 (M-H).sup.+ ; calculated for C.sub.22 H.sub.27 N.sub.3
O.sub.3.0.5H.sub.2 O: C,67.7; H,7.2; N,10.8. Found: C,67.6;H,7.1; N,10.7%.
EXAMPLE 232
Methyl 6-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!pyridine-3-carbxylate
To a suspension of 4-((4-pyridyl)piperazin-1-yl)phenol (1.13 g) in DMF (10
ml) was added a 60% dispersion of sodium hydride in oil (195 mg) and the
resulting mixture was stirred for 20 minutes. A solution of methyl
6-chloronicotinate (758 mg) in DMF (2 ml was added and the mixture was
heated at 60.degree. C. for 2 hours. The mixture was partitioned between
ethyl acetate(100 ml) and water(20 ml). The organic layer was dried
(MgSO.sub.4) and evaporated to give an oil which was purified by flash
column chromatography on silica, eluting with methanol/dichloromethane
(5:95 v/v) to give the title compound as a solid (815 mg): mp
143.degree.-144.degree. C.; NMR (d.sub.6 DMSO) .delta. 3.2-3.35(4H,m),
3.45-3.55(4H,m), 3.85(3H,s), 6.9(2H,dd), 7.05-7.1(4H,m), 8.15-8.3(3H,m),
8.7(2H,d); m/e 391 (M+H).sup.+ ; calculated for C.sub.22 H.sub.22 N.sub.4
O.sub.3.0.25H.sub.2 O: C,66.9; H,5.7; N,14.2. Found: C,66.9; H,5.7;
N,14.1%.
EXAMPLE 233
6-4-4-(4-Pyridyl)piperazin-1yl!phenoxy!pyridine-3-carboxylic acid
In a similar manner to Example 57, but using the product of Example 232,
was prepared the title compound in 95% yield as a solid: mp
335.degree.-340.degree. C. (dec); NMR (d.sub.6 DMSO+ CF.sub.3 COOD)
.delta. 3.4-3.5(4H,m), 3.9-4.0(4H,m), 7.05(1H,d), 7.2(4H,s), 7.3(2H,d),
8.25-8.35(3H,m), 8.7(1H,d); m/e 376 (M+H).sup.+ ; calculated for C.sub.21
H.sub.20 N.sub.4 O.sub.3.0.25H.sub.2 O: C,66.2; H,5.4; N,-14.7. Found;
C,66.1;H,5.4; N,14.9%.
EXAMPLE 234
4-(4-Pyridyl)piperazin-1-yl!benzoylisonipecotic acid
In a similar manner to Example 57, but starting from ethyl
4-(4-pyridyl)piperazin-1-yl!benzoylisonipecotate, the title compound was
prepared in 26% yield as a solid; NMR (d.sub.6 DMSO+CF.sub.3 COOD)
.delta.1.4-1.65(2H,m), 1.8-1.95(2H,m), 2.95-3.15(3H,m), 3.4-3.55(4H,m),
3.8-3.9(4H,m), 3.9-4.1(2H,m), 6.95(2H,d), 7.2(2H,d), 7.3(2H,d),
8.25(2H,d); m/e 395 (M+H).sup.+ calculated for C.sub.22 H.sub.26 N.sub.4
O.sub.3.1.6CF.sub.3 CO.sub.2 H: C,52.5; H, 4.8; N, 9.7. Found: C, 52.4; H,
5.1; N, 9.8%.
The starting material was prepared as follows:
i) In a similar manner to Example 56 but using ethyl isonipecotate, ethyl
4-(4-pyridylpiperazin-1-yl!benzoylisoipecotate was prepared in 32% yield
as a solid; NMR (d.sub.6 DMSO) .delta. 1.2(3H,t), 1.4-1.6(2H,m),
1.8-1.9(2H,m), 2.55-2.7(1H,m), 2.95-3.1(2H,m), 3.2-3.5(10H,m), 4.1(2H,q),
6.85(2H,d), 7.0(2H,d), 7.3(2H,d), 8.2(2H,d); m/e 423 (M+H).sup.+ ;
calculated for C.sub.24 H.sub.30 N.sub.4 O.sub.3. 1.6H.sub.2 O: C,63.9; H
7.4; N, 12.4. Found: C, 64.1; H, 7.4; N, 11.9%.
EXAMPLE 235
4-(4-Pyridyl)piperazin-1-yl!benzoylnipecotic acid
In a similar manner to Example 57, but starting from ethyl
4-(4-pyridyl)piperazin-1-yl!benzoylnipecotate was prepared the title
compound in 35% yield as a solid; NMR (d.sub.6 DMSO) .delta.
1.4-1.75(3H,m), 1.9-2.1(1H,m), 2.3-2.5(1H,m), 2.85-3.15(2H,m),
3.4-3.5(4H,m), 3.8-3.9(4H,m), 4.0-4.3(2H,bm), 6.95(2H,d), 7.25(2H,d),
7.3(2H,d), 8.25(2H,d); m/e 395 (M+H).sup.+ ; calculated for C.sub.22
H.sub.26 N.sub.4 O.sub.3 1.6CF.sub.3 COOH: C, 52.5; H, 4.8; N, 9.7. Found:
C, 52.4; H, 4.5; N, 9.3%.
The starting material was prepared as follows:
i) In a similar manner to Example 56 but using ethyl nipecotate, was
prepared ethyl 4-(4-pyridyl)piperazin-1-yl!benzoylnipecotate in 35% yield
as a solid; NMR (d.sub.6 DMSO) .delta. 1.5(3H,t), 1.35-1.75(3H,m),
1.9-2.05(1H,m), -2.05(1H,m), 2.3-2.5(1H,m), 2.3-2.5(1H,m), 3.0-3.3(4H,m),
3.0-3.3(4H,m), 3.4-3.5(4H,m), 4.05(2H,q), 6.85(2H,d), 6.95(2H,d),
7.25(2H,d), 8.15(2H,d); m/e 423 (M+H).sup.+ ; calculated for C.sub.24
H.sub.30 N.sub.4 O.sub.3.0.5H.sub.2 O: C, 66.8; H, 7.2; N, 13.0. Found C,
66.4; H, 7.3; N, 13.1%.
EXAMPLE 236
3-4-4-(4-Pyridyl)piperazin-1-yl!!-N-benzylbenzamidopropionic acid
In a similar manner to Example 57, but starting from methyl
3-4-4-(4-pyridyl)-piperazin-1-yl!!-N-benzylbenzamido propionate was
prepared the title compound in 72% yield as a solid; NMR (d.sub.6 DMSO)
.delta.2.5-2.6(2H,m), 3.4-3.55(6H,m), 3.75-3.85(4H,m), 4.65(2H,s),
6.95(2H,d), 7.15(2H,d), 7.2-7.45(7H,m), 8.25(2H,d); m/e 445 (M+H).sup.+ ;
calculated for C.sub.26 H.sub.28 N.sub.4 O.sub.3.0.5H.sub.2 O: C, 68.8; H,
6.3; N, 12.3. Found: C, 69.2; H, 5.8; N, 12.4%.
The starting material was prepared as follows:
In similar manner to Example 56, but using N-benzyl .beta.-alanine methyl
ester, was prepared methyl
3-4-(4-pyridyl)piperazin-1yl!!-N-benzylbenzamido propionate in 34% yield
as a solid; NMR (CDCl.sub.3) .delta.2.0-2.1(2H,m), 2.6-2.7(2H,t),
3.35-3.4(4H,m), 3.45-3.55(4H,m), 3.65(3H,s), 4.65(2H,s), 6.7(2H,d),
6.85(2H,d), 7.2-7.45(7H,m), 8.2-8.35(2H,m); m/e 459 (M+H).sup.+.
EXAMPLE 237
3-4-4-(Pyridyl)piperazin-1-yl!phenoxy!cyclohexane carboxylic acid
In a similar manner to Example 57, but starting from methyl
3-4-4-(4-pyridyl)-piperazin-1-yl!phenoxy!cyclohexylcarboxylate, was
prepared the title compound in 60% yield as a solid; NMR (d.sub.6 DMSO)
.delta. 1.2-1.5(4H,m), 1.5-1.9(2H,m), 2.0-2.1(1H,m), 2.25-2.3(2H,m),
2.35-2.45(1H,m), 3.2-3.25(4H,m), 3.3-3.35(4H,m), 6.85-7.0(4H,m),
7.2(2H,d), 8.2(2H,d); m/e 396 (M+H).sup.+ ; calculated for C.sub.22
H.sub.27 N.sub.3 O.sub.3.0.5H.sub.2 O: C,67.6; H, 7.2; N, 10.7 Found: C,
67.9; H, 7.2; N, 10.9%.
The starting material was prepared as follows:
i) In a similar manner to Example 230, but using methyl 3-hydroxy
cyclohexane carboxylate, was prepared methyl
3-4-4-(4-pyridyl)piperazin-1yl!phenoxy!cyclohexyl carboxylate in 8%
yield as solid; NMR (d.sub.6 DMSO) .delta. 1.25-1.6(4H,m), 185-2.0(2H,m),
2.05-2.2(1H,m), 2.3-2.45(2H,m), 3.15-3.25(4H,m), 4H,m), 3.45-3.55(4H,m),
3.65(3H,s), 4.05-4.15(1H,m), 6.7(2H,d), 6.8-7.0(4H,m), 8.3(2H,d); m/e 396
(M+H).sup.+.
EXAMPLE 238
4-4-4-(Pyridyl)piperazin-1 -yl!phenoxy!piperidineacetic acid
In a similar manner to Example 18, but starting from tert-butyl
4-4-4-(pyridyl)-piperazin-1-yl!phenoxypiperidinyl acetate, was prepared
the title compound in 77% yield as a solid; NMR (d.sub.6 DMSO) .delta.
1.85-2.2(4H,m), 3.15-3.25(4H,m), 3.25-3.45(4H,m), 3.8-3.9(4H,m),
4.15(2H,s), 4.55(1H,m), 6.95(4H,s), 7.25(2H,d), 8.25(2H,d); m/e 397
(M+H).sup.+ ; calculated for C.sub.22 H.sub.28 N.sub.4 O.sub.3.2.CF.sub.3
COOH.2.H.sub.2 O: C, 47.3; H, 5.1; N, 8.45. Found: C, 47.3; H, 4.8; N, 8%.
The starting material was prepared as follows:
i) In a similar manner to Example 230, but using tert-butyl
4-hydroxypiperidinyl acetate, was prepared tert-butyl
4-4-4-(pyridyl)piperazin-1-yl!phenoxypiperidinyl acetate in 35% yield as
a solid; NMR (d.sub.6 DMSO+CD.sub.3 COOD) .delta. 1.4(9H,s),
1.6-1.75(2H,m), 1.8-2.0(2H,m), 2.4-2.65(2H,m), 2.8-2.9(2H,m),
3.15-3.25(4H,m), 3.25(2H,s), 3.75-3.8(4H,m), 4.2-4.3(1H,m),
6.85-7.0(4H,m), 7.15(2H,d), 8.2(2(2H,d); m/e 453 (M+H).sup.+ ; calculated
for C.sub.26 H.sub.36 N.sub.4 O.sub.3.0.5H.sub.2 O: C,67.7; H, 8.0; N,
12.1. Found: C, 67.9; H, 8.3; N, 12.1%.
EXAMPLE 239
3-4-4-(4-Pyridyl)piperazin-1-yl!phenoxy!poperidineacetic acid
In a similar manner to Example 18, but starting from tert-butyl
3-4-4-(pyridyl)-piperazin-1yl!phenoxy!piperidinyl acetate was prepared
the title compound in 75% yield as a solid; NMR (d.sub.6 DMSO) .delta.
1.7-2.3(4H,m), 3.2-3.4(4H,m), 3.9-4.05(4H,m), 4.1(2H,s), 4.1-4.45(4H,m),
4.75-4.85(1H,m), 7.0(2H,d), 7.25-7.4(4H,m), 8.3(2H,d); m/e 397 (M+H).sup.+
The starting material was prepared as follows:
i) In a similar manner to Example 230, but using tert-butyl
3-hydroxypiperidinyl acetate, was prepared tert-butyl
3-4-4-(pyridyl)piperazin-1-yl!phenoxy!piperidinyl acetate in 17% yield
as an oil; NMR (d.sub.6 DMSO) .delta. 1.4(9H,d), 1.6-1.8(2H,m),
1.85-2.0(1H,m), 2.2-2.3(1H,m), 2.5-2.7 (2H,m), 2.95-3.05(2H,m),
3.05-3.15(4H,m), 3.4-3.5(4H,m), 3.65-3.9(2H,m), 4.1-4.25(1H,m),
6.8-6.95(6H,m), 8.2(2H,d); m/e 453 (M+H) .sup.+.
EXAMPLE 240
2-Propyl-4- 2-4-(4-pyridyl)piperazin-2-one-1-yl!acetyl!!phenoxyacetic
acid
Using the method of Example 202 but starting from methyl 2-.sup.n
propyl-phenoxyacetate, was prepared the title compound: NMR (d.sub.6 DMSO)
.delta. 0.9(3H,t), 1.55-1.7(2H,m), 2.65(2H,t), 3.45-3.55(2H,m),
365-3.75(2H,m), 4.05(2H,s), 4.9(2H,s), 6.85(2H,d), 6.9(1H,d), 7.75
-7.85(2H,m), 8.2(2H,d); m/e 412 (M+H).sup.+ ; calculated for C.sub.22
H.sub.25 N.sub.3 O.sub.5.0.25H.sub.2 O: C, 63.5; H, 6.1; N, 10.1. Found:
C, 63.5; H, 6.2; N, 9.9%.
The starting material was prepared as follows:
i) In a similar manner to Example 3i), but starting from 2-allyl phenol,
was prepared methyl 2-allyl-phenoxyacetate as an oil in 97% yield; NMR
(d.sub.6 DMSO) .delta. 3.45(2H,d), 3.7(3H,s), 4.8(2H,s), 5.0-5.1(2H,m),
5.9-6.1(1H,m), 6.85-6.95(2H,m), 7.1-7.2(2H,m); m/e 207 (M+H).sup.+.
ii) The product of step i) (5.86 g) was dissolved in methanol (100 ml) and
a catalytic amount of 10% palladium on carbon was added. The mixture was
hydrogenated at atmospheric pressure for 18 hours. The mixture was
filtered and concentrated to an oil which was purified by flash column
chromatography, eluting with ethyl acetate/hexane (10:90 v/v) to give
methyl 2-.sup.n propyl-phenoxyacetate (4.82 g) as an oil; NMR (d.sub.6
DMSO) .delta. 1.4(3H,t), 1.5-1.7(2H,m), 2.6(2H,t), 3.7(3H,s), 4.8(2H,s),
6.8-6.95(2H,m), 7.1-7.2(2H,m); m/e 208 (M).sup.+.
EXAMPLE 241
2-Methyl-4-2-4-(4-pyridyl)piperazin-2-one-1-yl!acetyl!!phenoxyacetic
acid
In a similar manner to Example 202, but starting from methyl
2-methylphenoxyacetate, was prepared the title compound as a solid; NMR
(d.sub.6 DMSO+CD.sub.3 COOD) .delta. 2.3(3H,s), 3.6-3.7(2H,m), 4.35(2H,s),
4.8(2H,s), 4.95(2H,s), 6.95(1H,d), 7.15(2H,d), 7.8-7.9(2H,d); m/e 384
(M+H).sup.+ ; calculated for C.sub.20 H.sub.21 N.sub.3 O.sub.5.1H.sub.2 O:
C, 59.8; H, 5.8; N, 10.0. Found: C, 59.3; H, 5.8: N, 10.1%.
EXAMPLE 242
Ethyl 4-4-4-(4-pyridyl)piperazin-2-one-1yl!phenoxy!butyrate
In a similar manner to that described in Example 50, but starting from
4-4-(4-pyridyl)piperazin-2-one-1-yl! phenol, the title compound was
prepared as a colourless solid (100 mg); NMR (d.sub.6 DMSO)
.delta.1.2(3H,t); 1.9-2.05(2H,q); 2.45(2H,t); 3.85(2H,m); 3.95(2H,m+2H,t);
4.05(2H,q); 4.4(2H,s); 6.9(2H,d); 7.15(2H,d); 7.25(2H,d); 8.25(2H,d); m/e
384 (M+H).sup.+.
The starting material was prepared as follows:
i) To a stirred suspension of 4-(4-pyridly)piperazin-2-one (880 mg) in
dimethyl formamide (20 ml) was added potassium hydride (1.0 ml of a 20%
dispersion) and the mixture stirred for 0.5 hr, after which time was added
copper (I) iodide (1.0 g). After 0.25 hr there was added
4-benzyloxybromobenzene (1.2 g) and the mixture stirred at 140.degree. C.
in an argon atmosphere for 2 hr. The reaction mixture was diluted with
water and brine and extracted with dichloromethane (3.times.40 ml); the
combined extracts were washed with water and brine, dried (PS paper) and
evaporated to give crude product as a pasty solid (2.0 g). This was
purified by flash chromatography on silica, eluting with
dichloromethane/methanol/conc. ammonia (97.5:0.5 v/v) to give 4-benzyloxy
4-(4-pyridyl)piperazin-2-one-1-yl!benzene as a colourless solid (1.1 g)
NMR .delta. (d.sub.6 DMSO) 3.7-3.9(4H,m); 4.1(2H,s); 5.1(2H,s);
6.85(2H,d); 7.05(2H,d); 7.25(2H,d); 7.3-7.6(5H,m); 8.2(2H,d); m/e 360
(M+H).sup.+.
ii) To a solution of the product of step i) (1.1 g) in a mixture of
methanol (500 ml) and tetrahydrofuran (100 ml) was added 30%
palladium-on-charcoal catalyst (300 mg) and the mixture stirred in an
atmosphere of hydrogen at ambient temperature and pressure until all the
starting material had been consumed. After removal of the catalyst by
filtration, the solvent was evaporated in vacuo to give
4-4-(4-pyridyl)piperazin-2-one-1-yl! phenol as a colourless solid,
essentially one spot by tlc, which was used without further purification
or characterisation.
EXAMPLE 243
4-4-4-(4-Pyridyl)piperazin-2-one-1-yl!phenoxy!butyric acid
In a manner similar to that described in Example 51, but starting from the
product of Example 242, the title compound was prepared as a colourless
soil (94 mg); NMR (d.sub.6 DMSO) .delta. 1.8-2.0(2H,q); 2.35(2H,t);
3.7-4.0(4H,m+2H,t); 4.3(2H,s); 6.85(2H,d); 7.05(2H,d; 7.2(2H,d);
8.15(2H,d); m/e 356 (M+H).sup.+.
EXAMPLE 244
4-2-Nitro-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyric acid
In a similar manner to Example 51, but starting from the compound of
Example 217, the title compound was obtained in 68% yield as a solid; m.p.
219.degree.-220.degree. C.; NMR (d.sub.6 DMSO) .delta. 8.2(2H,d),
7.4(1H,d), 7.27(2H,m), 6.98(2H,d), 4.08(2H,t), 3.23(4H,brt), 2.36(2H,t),
1.69(2H,m); m/e 387(M+H).sup.+. Calculated for C.sub.19 H.sub.22 N.sub.4
O.sub.5. H.sub.2 O: C, 56.4; H, 5.98; N, 13.9. Found: C, 56.7; H, 5.7; N,
13.9%.
EXAMPLE 245
(S)-3-1-1-(4-
Pyridyl)piperidin-4-yl!hexahydro-2oxodiazepin-4-carboxamido!propionic
acid, trifluoroacetate
In a similar manner to Example 189, methyl
(S)-3-1-1-(4-pyridyl)piperidin-4-yl!-hexahydro-2-oxodiazepin-4-carboxami
do!propionate (72 mg), methanol (5 ml) and sodium hydroxide solution (1N,
0.36 ml) gave, after preparative rp-hplc and lyophilisation, the title
compound (81 mg) a an off-white glassy solid: NMR (d.sub.6 DMSO) .delta.
1.70(8H,m), 2.40(2H,t), 3.20(6H,m), 3.65(1H,m), 4.12(1H,m), 4.29(2H,m),
5.58(1H,d), 7.20(2H,d, 8.00(1H,t), 8.19(2H,d), 13.25(1H,brs); m/Z 390
(M+H).sup.+ ; calculated for C.sub.19 H.sub.27 N.sub.5 O.sub.4. 1.5
CF.sub.3 CO.sub.2 H. 1.0 H.sub.2 O: C, 45.7%; H, 5.3%; N, 12.1%; found: C,
45.8%; H, 5.2%; N, 12.0%.
The starting material was prepared as follows:
A mixture of 1,4-dioxa-8-azaspiro4,5!decane (51.2 ml), 4-chloropyridine
hydrochloride (20 g) and potassium carbonate (18.4 g) in isoamyl alcohol
(400 ml) was gently refluxed for 18 hr. The reation mixture was cooled and
filtered. The filtrate was evaporated to give a waxy solid which was
triturated with hexane to give
8-(4-pyridyl)-1,4-dioxa-8-azaspiro!4,5!decane (24.16 g) as a colourless
solid; NMR (d.sub.6 DMSO) .delta. 1.65-1.70(4H,m), 3.45-3.55(4H,m),
3.9(4H,s), 6.90(2H,m), 8.15(2H,m); m/Z 221 (M+H).sup.+.
ii) A solution of 8-(4-pyridyl)-1,4-dioxa-8-azaspiro4,5!decane (10 g) in
2N sulphuric acid (140 ml) and tetrahydrofuran (70 ml) was stirred for 72
hr. The reaction was quenched with water (700 ml) and extracted with
dichloromethane (400 ml). The organic extracts were dried (MgSO.sub.4) and
evaporated to give a yellow solid which was purified by flash
chromatography on silica, eluting with methanol/dichloromethane (10:90
v/v) to give 1-(4-pyridyl)-4-oxopiperidine as a solid (3.97 g); m.p.
101.degree.-104.degree. C.; NMR (d.sub.6 DMSO) .delta. 2.45(4H,t),
3.75(4H,t), 6.85(2H,m), 8.20(2H,m); m/e 177 (M+H).sup.+.
To a stirred solution of N.sup..alpha.- Z-L-ornithine, tert-butyl ester
(preparation described in Milewska, M. J. et al (1990), Synthesis, 233-4)
(1.56 g) and 1-(4-pyridyl)-4-oxopiperidine (0.94 g) in methanol (50 ml) at
room temperature was added sodium cyanoborohydride (0.30 g). acetic acid
was added dropwise with stirring until the pH of the reaction mixture was
5. The reaction mixture was stirred for 2 hr at room temperature then
evaporated to near dryness. The residue was partitioned between saturated
aqueous sodium carbonate solution (50 ml) and ethyl acetate (100 ml). The
organic layer was separated, washed with brine, dried (MgSO.sub.4) and
evaporated. The residue was purified by flash chromatography on silica,
eluting with methanol/dichloromethane/concentrated ammonia, 10:90:0.1 to
10:90:0.2, to give tert. butyl
(S)-2-(benzyloxycarbonyl)amino-5-1-(4-pyridyl)piperidin-4yl!aminopentanoa
te (1.35 g) as a yellow gum: NMR (d.sub.6 DMSO) .delta. 1.22(9H,s),
1.70(6H,m), 1.97(2H,m), 2.85(4H,m), 3.22(1H,m), 3.75(1H,m), 4.06(2H,m),
4.90(2H,d), 6.93(2H,d), 7.20(5H,m), 8.06(2H,d); m/Z 483 (M+H).sup.+.
iv) To a solution of the product of step iii) (1.34 g) and acetic acid
(0.48 ml) in methanol under argon was added 10% Pd on C (100 mg). The
mixture was covered with a blanket of hydrogen and stirred at room
temperature for 4 hr. The catalyst was then removed by filtration through
a pad of kieselguhr and the pH of the filtrate was adjusted to 4 by
addition of acetic acid. To this mixture, under argon, was then added a
further quantity of 10% Pd on C (100 mg), it was covered again with
hydrogen and stirred at room temperature for 3 days. The catalyst was
filtered off through a pad of kieselguhr and the filtrate was evaporated
to dryness. Toluene (100 ml) was then added to the residue and the
solvents were again removed in vacuo to give tert. butyl
(S)-2-amino-5-1-(4-pyridly)piperidin-4-yl!-aminopentanoate, triacetate
salt (1.68 g) as a yellow gum: NMR (d.sub.6 DMSO+CD.sub.3 CO.sub.2 D)
.delta. 1.49(9H,s), 1.70(6H,m), 2.23(2H,m), 3.03(2H,m), 3.25(2H,m),
3.50(1H,m), 3.96(1H,m), 4.30(2H,m), 7.18(2H,d), 8.20(2H,d) m/Z 349
(M+H).sup.+.
v) To a mixture of the product of step iv) (1.65 g) triethylamine (1.2 ml)
and tetrahydrofuran (15 ml) was added with stirring carbonyl diimidazole
(0.5 g). The resultant reaction mixture was stirred at room temperature
for 20 hr then at reflux for 4 hr. The solvents were then removed in vacuo
and the residue was dissolved in dichloromethane, washed with water and
brine, dried (MgSO.sub.4) and evaporated to dryness. The residue was
purified by flash chromatography on silica, by elution with
methanol/dichloromethane (15% v/v to 25% v/v) to give a yellow gum, which,
on trituration with ether gave tert. butyl
(S)-1-1-(4-pyridly)piperidin-4-yl!hexahydro-2-oxodiazepin-4-carboxylate
(257 mg) as a white solid: NMR (d.sub.6 DMSO+CD.sub.3 CO.sub.2 D) .delta.
1.37(9H,s), 1.70(8H,m), 3.10(4H,m), 3.78(1H,m), 4.11(1H,m), 4.21(2H,m),
7.06(2H,d), 8.08(2H,d); m/Z 375 (M+H).sup.+.
vi) A solution of the product of step v) (219 mg) in trifluoroacetic acid
(5 ml) was stirred at room temperature for 90 min then evaporated to
dryness. The residue was triturated with ether and the resultant solid was
collected to give
(S)-1-1-(4-pyridyl)piperidin-4yl!-hexahydro-2-oxodiazepin-4-carboxylic
acid, trifluoroacetate salt (124 mg) as a cream-coloured solid: NMR
(d.sub.6 DMSO) .delta. 1.70(8H,m), 3.05(2H,m), 3.20(2H,m), 3.81(1H,m),
4.12(1H,m), 4.30(2H,m), 5.59(1H,d), 7.20(2H,d), 8.18(2H,d), 13.35(1H,brs)
m/Z 319 (M+H).sup.+.
vii) In a similar manner to Example 189i), the product of step vi), (210
mg), HBTU (203 mg), HOBt.H.sub.2 O (82 mg), DMF (5 ml),
diisoproylethylamine (0.47 ml) and methyl 3-aminopropionate, hydrochloride
(75 mg) gave, after purification by flash chromatography on alumina,
eluting solvent dichloromethane/methanol, 20:1, methyl
(S)-3-1-1-(4-pyridyl)piperidin-4-yl!hexahydro-2-oxodiazepin-4-carboxamid
o!propionate (78 mg) as a yellow gum: NMR (d.sub.6 DMSO) .delta.
1.70(8H,m), 2.45(2H,m), 2.88(2H,m), 3.06(2H,m), 3.32(2H,m), 3.63(4H,m),
4.02(3H,m), 5.52(1H,d), 6.81(2H,d), 8.03(1H,t), 8.12(2H,d); m/Z 404
(M+H).sup.+.
EXAMPLE 246
(-)-(3R)-3-Methyl-4-{4-4-(4-pyridyl)piperazin-1-yl!phenoxy}butyric acid
hydrochloride
Sodium hydride (60% dispersion in mineral oil, 2.44 g) was added to a
stirred suspension of 4-4-(4-pyridyl)piperazin-1-yl!phenol (15.5 g) in
dry DMF (120 ml) and the mixture stirred for 45 min. tert-Butyl
(3R)-3-methyl-4-(p-toluenesulphonyloxy)butyrate (20 g) was added and the
mixture stirred for 20 hours. The mixture was evaporated and the residue
partitioned between dichloromethane and water. The organic layer was
washed with water, filtered through phase separating paper (Whatman IPS)
and evaporated. The residue was triturated under diethyl ether. The solid
so obtained was recrystallised from ethyl acetate to give tert-butyl
(-)-(3-methyl-4-{4-4-(4-pyridyl)piperazin-1-yl!phenoxy}butyrate (10.6 g);
m.p. 112.degree.-113.degree. C.; alpha!.sub.D =-5.5.degree. (conc.=1
g/100 ml of methanol; 20.degree. C.); NMR (CDCl.sub.3) .delta. 8.3(2H,d),
6.89(4H,m), 6.7(2H,m), 3.79(2H,d), 3.46(4H,m), 3.28(4H,m),
2.31-2.53(2H,m), 2.08-2.21(1H,m), 1.44(9H,s), 1.07(3H,d).
A mixture of tert-butyl
(-)-(3R)-3-methyl-4-{4-4-(4-pyridyl)piperazin-1-yl!phenoxy}butyrate
(10.53 g) and 1N aqueous hydrochloric acid (250 ml) was stirred for 44
hours. 1N aqueous sodium hydroxide solution (250 ml) was added and the
mixture cooled to 5.degree. C. The mixture was filtered and the filtrate
evaporated. Water (150 ml) was added and the resultant precipitate
isolated and washed in turn with water, acetone and diethyl ether. The
material so obtained was stirred with 1N aqueous hydrochloric acid (25 ml)
for 16 hours. The mixture was cooled to 5.degree. C. and filtered. The
solid so obtained was washed in turn with water, acetone and diethyl ether
and dried to give
(-)-(3R)-3-methyl-4-{4-4-(4-pyridyl)piperazin-1-yl!phenoxy}butyric acid
hydrochloride (7.9 g); m.p. 203.degree.-205.degree. C.; alpha!.sub.D
=-6.2.degree. (conc.=1 g/100 ml of methanol; 20.degree. C.); NMR (d.sub.6
DMSO) .delta. 13.8(1H,br), 12.1(1H,br), 8.27(2H,d), 7.28(2H,d), 6.9(4H,m),
3.8(6H,m), 3.18(4H,t), 2.45(1H,m), 2.23(1H,m), 2.12(1H,m), 1.0(3H,d); m/e
356(M+H).sup.+ ; Calculated for C.sub.20 H.sub.25 N.sub.3
O.sub.3.HCl.H.sub.2 O: C, 58.5; H, 6.8; N, 10.2; Found: C, 58.3; H, 6.9;
N, 10.2%;
The chiral starting material was prepared as follows:
i) Sodium bis(trimethylsilyl)amide (1M in THF, 170 ml) was added dropwise
to a solution of (4S)-4-isopropyl-3-propionyloxazolidin-2-one (J. Am.
Chem. Soc., 1981, 103, 2127; 28.4 g) in dry THF (500 ml) which had been
cooled to -70.degree. C. and placed under an atmosphere of argon. The rate
of addition was adjusted such that the temperature of the reaction mixture
did not rise above -67.degree. C. The resultant solution was stirred at
-70.degree. C. for 30 min. tert-Butyl bromoacetate (42.3 g) was added
dropwise and the solution stirred at -70.degree. C. for 3 hours. The
solution was then allowed to warm to room temperature. The solvent was
evaporated and the residue partitioned between diethyl ether and water.
The organic phase was separated, filtered through phase separating paper
(Whatman IPD) and evaporated. The residue was triturated under hexane at
-40.degree. C. to give a solid (21.6 g). A second crop of solid (4.4 g)
was obtained by evaporation of the hexane solution and purification of the
residue by filtration chromatography on silica gel starting with hexane
and progressing to 1/10 ethyl acetate/hexane. The two batches of solid
were combined and recrystallised from hexane to give
(4S)-3-(2R)-3-tert-butoxycarbonyl-2-methylpropionyl!-4-isopropyloxazolidi
n-2-one (22.5 g); m.p. 64.degree.-65.degree. C.; NMR (CDCl.sub.3) .delta.
4.41(1H,m), 4.21(2H,m), 4.12(1H,m), 2.79(1H,m), 2.28-2.4(2H,m), 1.41(9H,s)
1.16(3H,d), 0.9(6H,m).
ii) Hydrogen peroxide (30%, 44 ml) and lithium hydroxide monohydrate (6.38
g) were added in turn to a stirred mixture of
(4S)-3-(2R)-3-tert-butoxycarbonyl-2-methylpropionyl!-4-isopropyloxazolidi
n-2-one (22.5 g), water (280 ml) and THF (800 ml) which had been cooled to
5.degree. C. The resultant mixture was stirred at 5.degree. C. for 3
hours. A saturated aqueous sodium metabisulphite solution was added to
destroy the excess hydrogen peroxide and the solvent evaporated. The
residue was extracted with dichloromethane. The aqueous solution was
acidified by the addition of an aqueous citric acid solution and extracted
with dichloromethane. The extracts were combined, washed with water and
filtered through phase separating paper. The filtrate was evaporated to
give 1-tert-butyl (3R)-3-methyl-succinate as an oil (12.9 g); NMR
(CDCl.sub.3) .delta. 2.9(1H,m), 2.64(1H,m), 2.37(1H,m), 1.4(9H,s),
1.23(3H,d).
iii) Borane-dimethyl sulphide complex (10M, 10.3 ml) was added over 15 min
to a stirred mixture of 1-tert-butyl (3R)-3-methylsuccinate (12.9 g) and
THF (200 ml) which had been cooled to -10.degree. C. and placed under an
atmosphere of argon. The mixture was stirred at -10.degree. C. for 30 min.
The mixture was allowed to warm to room temperature and stirred for 1
hour. The mixture was recooled to 5 C. and methanol (50 ml) was added
portionwise. The mixture was allowed to warm to room temperature and
stirred for 30 min. The mixture was evaporated and the residue partitioned
between dichloromethane (100 ml) and water (100 ml). The organic phase was
filtered through phase separating paper and evaporated to give tert-butyl
(3R)-4-hydroxy-3-methylbutyrate as an oil (11 g); NMR (CDCl.sub.3) .delta.
3.55(2H,m), 2.1-2.4(3H,m), 1.46(9H,s), 0.98(3H,d).
iv) p-Toluenesulphonyl chloride (13.2 g) was added portionwise to a stirred
mixture of tert-butyl (3R)-4-hydroxy-3-methylbutyrate (11 g),
triethylamine (21 ml) and dichloromethane (120 ml) and the mixture stirred
for 20 hours. The mixture was washed in turn with water and dilute aqueous
sodium carbonate solution. The organic solution was filtered through phase
separating paper and evaporated to give tert-butyl
(3R)-3-methyl-4-(p-toluenesulphonyloxy)butyrate as an oil (20 g); NMR
(CDCl.sub.3) .delta. 7.6(2H,d), 7.33(2H,d), 3.92(2H,d), 2.45(3H,s),
2.18-2.47(2H,m), 2.0-2.15(1H,m), 1.42(9H,s), 0.95(3H,d).
EXAMPLE 247
Illustrative pharmaceutical dosage forms suitable for presenting the
compounds of the invention for therapeutic or prophylactic use include the
following, which may be obtained by conventional procedures well known in
the art.
______________________________________
a) Tablet I mg/tablet
______________________________________
Active ingredient
1.0
Lactose Ph. Eur.
93.25
Croscarmellose sodium
4.0
Maize starch paste
0.75
(5% w/v aqueous paste)
Magnesium stearate
1.0
______________________________________
b) Tablet II mg/tablet
______________________________________
Active ingredient
50
Lactose 223.75
Croscarmellose sodium
6.0
Maize starch 15.0
Polyvinylpyrrolidone
2.25
(5% w/v aqueous paste)
Magnesium stearate
3.0
______________________________________
c) Tablet III mg/tablet
______________________________________
Active ingredient
100
Lactose 182.75
Croscarmellose sodium
12.0
Maize starch paste
2.25
(5% w/v aqueous paste)
Magnesium stearate
3.0
______________________________________
(d) Capsule mg/capsule
______________________________________
Active ingredient
10
Lactose Ph. Eur.
488.5
Magnesium stearate
1.5
______________________________________
(e) Injection mg/ml
______________________________________
Active ingredient
1.0
(acid addition salt)
Sodium chloride
9.0
Purified water to 1.0 ml
______________________________________
EXAMPLE 248
The following is a description of a study of the effects of the (-)-(3R)
compound of Example 246 and the corresponding (3RS)-racemic mixture of
Example 203 in the rat. Four groups of ten Alderley Park Wistar rats (each
group comprising 5 male and 5 female rats) were dose orally with the
(3RS)-racemic mixture of Example 203 at daily doses of 0, 25, 100 or 500
mg/kg. Dosing was continued for a total of seven days. The animals were
killed and examined. Adverse effects were noted in the livers of six of
the group of ten rats dosed at 500 mg/kg/day.
Four groups of ten Alderley Park Wistar rats (each group comprising 5 male
and 5 female rats) were dosed orally with the (-)-(3R) compound of Example
246 at daily doses of 0, 50, 250 and 1000 mg/kg. The highest dose was not
tolerated. After four or five days, four of the animals from this group
were killed. The remaining six animals were dosed at 500 mg/kg/day for the
remainder of the study. Dosing was continued for a total of fourteen days.
The animals were killed and examined. No adverse effects were noted in the
livers of the group of rats dosed at 250 mg/kg/day. The six animals dosed
at 1000 mg/kg/day for three or four days and then at 500 mg/kg/day for ten
or eleven days also showed no adverse effect on the liver.
Based on such observations, it is seen that the (-)-(3R) compound of
Example 246 causes no significant adverse effect on the rat liver at 500
mg/kg/day.
By implication, the (-)-(3R) compound of Example 246 is less toxic than the
(3RS)-racemic mixture of Example 203.
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